Aryl-substituted bridged or fused diamines as modulators of leukotriene A4 hydrolase

ABSTRACT

Aryl-substituted bridged or fused diamine compounds, pharmaceutical compositions containing them, and methods of using the compounds and the pharmaceutical compositions for leukotriene A 4  hydrolase (LTA 4 H or LTA4H) modulation and for the treatment of disease states, disorders, and conditions mediated by LTA 4 H activity, such as allergy, asthma, autoimmune diseases, pruritis, inflammatory bowel disease, ulcerative colitis, and cardiovascular disease, including atherosclerosis and prevention of myocardial infarction.

This application is a divisional of U.S. application Ser. No.12/291,018, filed on Oct. 30, 2008, now U.S. Pat. No. 7,935,725 whichclaims the benefit of U.S. provisional patent application Ser. No.60/984,126, filed Oct. 31, 2007, all of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to certain aryl-substituted bridged orfused diamine compounds, pharmaceutical compositions containing them,and methods of using the compounds and pharmaceutical compositions forleukotriene A₄ hydrolase (LTA₄H or LTA4H) modulation and for thetreatment of disease states, disorders, and conditions mediated byLTA₄H.

BACKGROUND OF THE INVENTION

Inflammation is normally an acute response by the immune system toinvasion by microbial pathogens, chemicals or physical injury. In somecases, however, the inflammatory response can progress to a chronicstate, and be the cause of inflammatory disease. Therapeutic control ofthis chronic inflammation in diverse diseases is a major medical need.

Leukotrienes (LT) are biologically active metabolites of arachidonicacid (B. Samuelsson, Science 1983, 220(4597): 568-575) that have beenimplicated in inflammatory diseases, including asthma (D. A. Munafo etal., J. Clin. Invest. 1994, 93(3):1042-1050; N. Miyahara, et al.,Allergol Int., 2006, 55(2): 91-7; E. W. Gelfand, et al., J. AllergyClin. Immunol. 2006, 117(3): 577-82; K. Terawaki, et al., J. Immunol.2005, 175(7): 4217-25), inflammatory bowel disease (IBD) (P. Sharon andW. F. Stenson, Gastroenterology 1984, 86(3): 453-460), chronicobstructive pulmonary disease (COPD) (P. J. Barnes, Respiration 2001,68(5): 441-448), arthritis (R. J. Griffiths et al., Proc. Natl. Acad.Sci. U.S.A. 1995, 92(2): 517-521; F. Tsuji et al., Life Sci. 1998,64(3): L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci. 1999, 21(3):135-146; Y. I. Zhu and M. J. Stiller, Skin Pharmacol. Appl. SkinPhysiol. 2000, 13(5):235-245) and atherosclerosis (Friedrich, E. B. etal. Arterioscler Thromb Vasc Biol 23, 1761-7 (2003); Subbarao, K. et al.Arterioscler Thromb Vasc Biol 24, 369-75 (2004); Helgadottir, A. et al.Nat Genet. 36, 233-9 (2004); Jala, V. R. et al Trends in Immun. 25,315-322 (2004)). The synthesis of leukotrienes is initiated by theconversion of arachidonic acid to an unstable epoxide intermediate,leukotriene A4 (LTA4), by 5-lipoxygenase (5-LO) (A. W. Ford-Hutchinsonet al., Annu. Rev. Biochem. 1994, 63: 383-347). This enzyme is expressedpredominantly by cells of myeloid origin, particularly neutrophils,eosinophils, monocytes/macrophages and mast cells (G. K. Reid et al., J.Biol. Chem. 1990, 265(32): 19818-19823). LTA4 can either be conjugatedwith glutathione by leukotriene C4 (LTC4) synthase to produce thecysteinyl leukotriene, LTC4, or hydrolyzed to the diol, leukotriene B4(LTB4) (B. Samuelsson, Science 1983, 220(4597): 568-575). LTC4 and itsmetabolites, LTD4 and LTE4, induce smooth muscle contraction,broncho-constriction and vascular permeability, while LTB4 is a potentchemo-attractant and activator of neutrophils.

The stereospecific hydrolysis of LTA4 to LTB4 is catalyzed byleukotriene A4 hydrolase (LTA₄H), a zinc-containing, cytosolic enzyme.This enzyme is ubiquitously expressed, with high levels in smallintestinal epithelial cells, lung, and aorta (B. Samuelsson and C. D.Funk, J. Biol. Chem. 1989, 264(33): 19469-19472). Moderate expression ofLTA₄H is observed in leukocytes, particularly neutrophils (T. Yokomizoet al., J. Lipid Mediators Cell Signalling 1995, 12(2,3): 321-332).

Leukotriene B4 is a key pro-inflammatory mediator, able to recruitinflammatory cells, such as neutrophils and eosinophils, as well asactivate neutrophils (F. A. Fitzpatrick et al., Ann. N.Y. Acad. Sci.1994, 714: 64-74; S. W. Crooks and R. A. Stockley, Int. J. Biochem. CellBiol. 1998, 30(2): 173-178; A. Klein et al., J. Immunol. 2000, 164:4271-4276). LTB4 mediates its pro-inflammatory effects by binding to Gprotein-coupled receptors, leukotriene B4 receptor 1 (BLT1) andleukotriene B4 receptor 2 (BLT2) (T. Yokomizo et al., Arch. Biochem.Biophys. 2001, 385(2): 231-241). The receptor first identified, BLT1,binds LTB4 with high affinity, leading to intracellular signaling andchemotaxis. BLT1 is expressed mainly in peripheral leukocytes,particularly neutrophils, eosinophils, macrophages (Huang, W. W. et al.J Exp Med 188, 1063-74 (1998)) and monocytes (Yokomizo, T., Izumi, T. &Shimizu, T. Life Sci 68, 2207-12 (2001)). The murine receptor is alsoexpressed on effector T cells and was recently shown to mediateLTB4-dependent migration of effector CD8⁺ T cells (Goodarzi, K.,Goodarzi, M., Tager, A. M., Luster, A. D. & von Andrian, U. H. NatImmunol 4, 965-73 (2003); Ott, V. L., Gambier, J. C., Kappler, J.,Marrack, P. & Swanson, B. J. Nat Immunol 4, 974-81 (2003)), earlyeffector CD4⁺ T helper type 1 (T_(H)1) and T_(H)2 chemotaxis andadhesion to endothelial cells, as well as early effector CD4⁺ and CD8⁺ Tcell recruitment in an asthma animal model (Tager, A. M. et al., NatImmunol 4, 982-90 (2003)). LTB4 receptor BLT2 (S. Wang et al., J. Biol.Chem. 2000, 275(52): 40686-40694; T. Yokomizo et al., J. Exp. Med. 2000,192(3): 421-431) shares 42% amino acid homology with BLT1, but is morebroadly expressed, including in peripheral tissues such as the spleen,ovary and liver, as well as in leukocytes. BLT2 binds LTB4 with loweraffinity than BLT1 does, mediates chemotaxis at higher concentrations ofLTB4, and differs from BLT1 in its affinity for certain antagonists.While LTB4 receptor antagonists may differ in their affinity for BLT1versus BLT2, blocking the production of LTB4 using LTA₄H inhibitorswould be expected to inhibit the downstream events mediated through bothBLT1 and BLT2.

Studies have shown that introduction of exogenous LTB4 into normaltissues can induce inflammatory symptoms (R. D. R. Camp et al., Br. J.Pharmacol. 1983, 80(3): 497-502; R. Camp et al., J. Invest. Dermatol.1984, 82(2): 202-204). Elevated levels of LTB4 have been observed in anumber of inflammatory diseases including IBD, COPD, psoriasis,rheumatoid arthritis (RA), cystic fibrosis and asthma (S. W. Crooks andR. A. Stockley, Int. J. Biochem. Cell Biol. 1998, 30(2): 173-178).Therefore, reduction of LTB4 production by an inhibitor of LTA₄Hactivity would be predicted to have therapeutic potential in a widerange of diseases.

This idea is supported by a study of LTA₄H-deficient mice that, whileotherwise healthy, exhibited markedly decreased neutrophil influx inarachidonic acid-induced ear inflammation and zymosan-inducedperitonitis models (R. S. Byrum et al., J. Immunol. 1999, 163(12):6810-6819). LTA₄H inhibitors have been shown to be effectiveanti-inflammatory agents in pre-clinical studies. For example, oraladministration of LTA₄H inhibitor SC57461 caused inhibition ofionophore-induced LTB4 production in mouse blood ex vivo, and in ratperitoneum in vivo (J. K. Kachur et al., J. Pharm. Exp. Ther. 2002,300(2), 583-587). Eight weeks of treatment with the same inhibitorcompound significantly improved colitis symptoms in cotton top tamarins(T. D. Penning, Curr. Pharm. Des. 2001, 7(3): 163-179). The spontaneouscolitis that develops in these animals is very similar to human IBD. Theresults therefore indicate that LTA₄H inhibitors would have therapeuticutility in this and other human inflammatory diseases.

Events that elicit the inflammatory response include the formation ofthe pro-inflammatory mediator leukotriene B4. Hydrolase LTA₄H catalyzesthe formation of this mediator, and LTA₄H inhibitors block theproduction of the pro-inflammatory mediator LTB4, thus providing theability to prevent and/or treat leukotriene-mediated conditions, such asinflammation. The inflammatory response is characterized by pain,increased temperature, redness, swelling, or reduced function, or by acombination of two or more of these symptoms. Regarding the onset andevolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disease thatusually occurs in individuals with a personal or family history ofatopy. The major features are pruritus and chronic or relapsingeczematous lesions. Complications include bacterial, fungal and viralinfections as well as ocular disease. Atopic dermatitis is the mostcommon inflammatory skin disease in children and affects more than 15%of children in the US (Laughter, D., et al., J. Am. Acad. Dermatol.2000, 43, 649-655). Atopic dermatitis may persist in 60% of adults whowere affected as children (Sidbury, R., et al., Dermatol. Clin. 2000,18(1), 1-11).

Atopic dermatitis has significant societal impact. The family stressrelated to caring for children with moderate to severe AD may becomparable to the stress seen in families of children with type Idiabetes mellitus (Su, J. C., et al., Arch. Dis. Child 1997, 76,159-162). In the US, the annual cost of medical services andprescription drugs for the treatment of AD/eczema is similar to thosefor emphysema, psoriasis and epilepsy (Ellis, C. N., et al., J. Am.Acad. Dermatol. 2002, 46, 361-370).

Topical corticosteroids and emollients are the standard of care in thetreatment of AD. However, topical steroids are associated with cutaneouscomplications such as striae, atrophy and telangeictasia that limit thelong-term use of these agents (Hanifin, J. M., et al., J. Am. Acad.Dermatol. 2004, 50, 391-404). Emollients have a steroid-sparing effectand are useful for both prevention and maintenance therapy. Crude coaltar and preparations containing coal tar derivatives have also been usedfor many years in the treatment of AD and have significant cosmeticdisadvantages that influence compliance (Hanifin, et al., 2004). Topicaldoxepin may be a useful short-term adjunctive therapy for the relief ofpruritus but sedation and contact dermatitis may complicate its use(Hanifin, et al., 2004).

The topical calcineurin inhibitors tacrolimus (Protopic®) andpimecrolimus (Elidel®) have been shown to reduce the extent, severityand symptoms of AD in adults and children and are approved for use assecond-line therapy of AD. However, the recent addition of boxedwarnings to the product labels regarding rare cases of malignancyreported in patients treated with topical calcineurin inhibitors limitslong term use of these agents in the treatment of AD (Food and DrugAdministration [FDA]/Center for Drug Evaluation and Research [CDER]resources page).

Antibiotics are used in the treatment of Staphylococcus aureusinfections in patients with AD but have a minimal effect on thedermatitis (Hanifin, et al., 2004). Although sedating antihistamines maybe useful if sleep disruption is present, oral antihistamines aregenerally not effective in treating AD-associated pruritus (Hanifin, etal., 2004). Ultraviolet (UV) phototherapy, including photochemotherapywith psoralen is well established in the treatment of AD but relapseupon cessation of therapy frequently occurs (Hanifin, et al., 2004).

Systemic immunomodulatory therapy with cyclosporine and corticosteroidsis effective but can be associated with severe side effects and isgenerally reserved for patients with severe disease. Systemiccorticosteroids are associated with growth retardation in children,avascular necrosis of bone, osteopenia, increased risk of infection,poor wound healing, cataracts, hyperglycemia and hypertension.Cyclosporine is nephrotoxic in a majority of patients and is associatedwith tremor, hirsutism, hypertension, hyperlipidemia and gumhyperplasia.

While AD that is mild to moderate in severity generally responds totopical therapy, correct use of these therapies and compliance remain amajor issue in the clinic. An oral or topical agent lacking the risksassociated with corticosteroids and the calcineurin inhibitors would bea welcome addition to the armamentarium of treatments for AD that ismild to moderate in severity. An effective oral or topical therapy withfewer side effects than systemic immunomodulatory therapies and potenttopical corticosteroids would fill an unmet medical need in thetreatment of AD.

LTB₄ is a potent pro-inflammatory lipid mediator derived fromarachidonic acid via the 5-lipoxygenase (5-LO) pathway. LTB₄ is known tobe a chemotactic factor and activator of leukocytes, particularlygranulocytes and T-cells, and has been implicated in several allergicand inflammatory diseases.

LTB₄ plays a role in AD. LTB₄ levels are elevated in skin lesions andplasma in AD. Reported in vivo and in vitro studies have shown thatleukotrienes, especially LTB₄, contribute to the inflammation of theskin in AD through their chemotactic effect on inflammatory cells. LTB₄receptors are expressed on mast cells, T cells, eosinophils, dendriticcells and macrophages, all of which accumulate in AD lesions. LTB₄itself is a pruritic agent, and has also been shown to mediate substanceP- and nociceptin-induced pruritus, a key component of the itching inAD. LTB₄ also induces proliferation of keratinocytes, an effect which isfurther potentiated by substance P. Recent reports indicate a role forLTB₄ in development of a Th2 immune response and IgE production. Therole of LTB₄ in AD is further supported by beneficial effects of the5-lipoxygenase inhibitor, zileuton, in a small open-label trial in AD(Woodmansee, D. P., et al., Ann. Allergy Asthma Immunol. 1999, 83,548-552) and in relieving the pruritus in Sjögren-Larsson syndromepatients who have elevated LTB₄ levels due to an impairment in itsdegradation (Willemsen, M. A., et al., Eur. J. Pediatr. 2001, 160,711-717).

Embodiments of this invention have shown dose-dependent inhibition ofdermal inflammation and pruritus in a number of preclinical models, aswell as inhibition of Th2 responses and IgE production. Oraladministration of embodiments of this invention inhibitedarachidonic-acid-induced ear inflammation (neutrophil influx and edema)in mice. In a mouse model of cutaneous contact hypersensitivity (CHS),dosing of embodiments of this invention around sensitization decreasedIgE production and skin edema upon antigen challenge, while dosing priorto challenge decreased pruritus. Oral dosing of embodiments of thisinvention was also efficacious in reducing pruritus in mice induced bycompound 48/80, substance P or IgE-antigen interaction in the skin.

LTA₄H inhibitors are hypothesized to specifically block the productionof LTB₄ from LTA₄, without affecting the biosynthesis of lipoxins, whichare also produced from LTA₄. Increasing or maintaining lipoxin A₄ (LXA₄)production may have beneficial therapeutic effects in dermalinflammation as it has been reported that topical application of astable lipoxin analogue inhibits edema, granulocyte infiltration andepidermal hyperproliferation in murine skin inflammation models. 5-LOinhibitors block the pathway upstream of LTA₄. This would be expected tolead to a block in not only synthesis of LTA₄, LTB₄ and cysteinylleukotrienes, but also LXA₄.

Embodiments of this invention have been studied in a number of in vivoskin (and peritoneal) inflammation models including arachidonicacid-induced ear inflammation, zymosan-induced peritonitis, fluoresceinisothiocyanate (FITC)-induced cutaneous contact hypersensitivity (CHS),and cutaneous itch induced by substance P, compound 48/80 andIgE/antigen interaction. Pharmacology models were also performed withembodiments of this invention to assess their effects on the developmentof Th2 immune responses and allergic lung inflammation, includingovalbumin (OVA) sensitization model and OVA sensitization and airwaychallenge models. Additional pharmacological profiling demonstratedefficacy in models of acute and chronic TNBS-induced colitis andcollagen-induced arthritis.

An allergy is an abnormal reaction to an allergen (an ordinarilyharmless substance) that triggers an abnormal response in a sensitizedindividual. Allergic rhinitis is an inflammation of the mucus membranesof the nose that occurs in response to an airborne antigen (allergen).Allergic rhinitis, also called allergic rhinoconjunctivitis, ischaracterized by frequent or repetitive sneezing, runny or congestednose, and pruritus of the nose, eyes and throat. It may also beassociated with other symptoms such as headache, impaired smell,postnasal drip, conjunctival symptoms (e.g., itchy watery eyes),sinusitis and other complicating respiratory symptoms. Depending uponthe time of exposure, allergic rhinitis can be classified as perennial,seasonal or occupational.

Embodiments of this invention have shown dose-dependent inhibition oflung inflammation in a number of pre-clinical models, as well asinhibition of Th2 responses and IgE production. In addition, embodimentsof this invention inhibit pruritus induced by allergen/IgE interaction.

Based upon the well-described leukotriene biosynthesis pathway (FIG. 1),LTA₄H inhibitors are hypothesized to specifically block the productionof LTB₄ from LTA₄, without affecting the biosynthesis of lipoxins, whichare also produced from LTA₄. Lipoxins, such as LXA₄, have been the focusof intense study and are known to play a key role as naturalanti-inflammatory agents and key mediators of the natural process ofresolving an inflammatory response. Furthermore, production ofendogenous LXA₄ has been described in a variety of inflammatory diseasesand lower levels of LXA₄ have been found in patients with severe versusmoderate asthma. These data are consistent with the proposition thatLXA₄ plays an important role in resolution of acute inflammation. UnlikeLTA₄ inhibitors, 5-LO inhibitors block this pathway upstream of LTA₄.This would lead to a block in not only synthesis of LTA₄, LTB₄ andcysteinyl leukotrienes, but also LXA₄. Furthermore, there is apossibility that LTA₄H inhibitors result in a buildup of LTA₄, andpathway shunting to pro-inflammatory cysteinyl leukotrienes, although todate there is no known data to support this possibility. Embodiments ofthis invention have shown in a model of zymosan-induced peritonitis thatinhibition of LTB₄ production leads to an increase in LXA₄ production.

Neutrophil infiltration is a prominent feature of severe asthma.Zileuton (Zyflo®) has been suggested to be efficacious is severe asthmapatients, while CysLT antagonists (i.e., Montelukast/Singulair®) arenot. Embodiments of this invention inhibit Th2 T cell responses and IgEproduction in animal models of asthma.

Embodiments of this invention inhibited sensitization to antigen andreduced inflammatory responses to airway allergen challenge insensitized mice, leading to dose-dependent decreases in airwayhyperreactivity, airway recruitment of inflammatory cells, andreductions in interleukin (IL)-5, IL-13, and antigen-specific IgEproduction.

In trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats,embodiments of this invention had significant inhibitory effects oncolonic inflammation, including macroscopic colonic injury, inflammatorycell content, and levels of tumor necrosis factor alpha (TNF-α), LTB₄,and IL-6. LTA₄H inhibition by embodiments of this invention alsosignificantly attenuated the joint inflammation and swelling associatedwith the destruction of collagen in murine models of arthritis.

Embodiments of this invention are expected to find utility in treatingskin burns, such as those due to sunburn or some other agent.

Embodiments of this invention are expected to find utility in treatingalso any one or a combination of atopic dermatitis, contact dermatitis,acne (T. Alestas, et al., J. Mol. Med. 2006, 84(1): 75-87; Ch. C.Zouboulis, et al., Dermatology, 2005, 210(1): 36-8; Arch. Dermatol.2003, 139(5): 668-70), myocardial infarction (A. Helgadottir, et al.,Nat. Genet. 2006, 38(1): 68-74; Nat. Genet. 2004, 36(3): 233-9; H.Hakonarson, et al., JAMA 2005, 293(18): 2245-56), stroke (A.Helgadottir, et al., Nat. Genet. 2004, 36(3): 233-9; F. C. Barone, etal., Mol. Chem. Neuropathol. 1995, 24(1): 13-30), pain (J. M. Cunha, etal., Br. J. Pharmacol. 2003, 139(6): 1135-45; S. W. Hwang, et al., Proc.Natl. Acad. Sci. USA 2000, 97(11): 6155-60), itch (T. Andoh, et al.,Eur. J. Pharmacol. 2006, 547(1-3): 59-64, 2000, 406(1): 149-152, 1998,353(1): 93-96); J. Investigativ. Dermatol. 2004, 123(1): 196-201, 2001,117(6): 1621-26; gingivitis (G. Emingil, et al., J. Periodontol. 2001,72(8): 1025-31), uveitis (T. Liao, et al., Invest. Ophthalmol. Vis. Sci.2006, 47(4): 1543-9), bronchitis (S. Gompertz, et al., Eur. Respir. J.2001, 17(6): 1112-9), allergic rhinitis, cystic fibrosis (G. E.Carpagnano, et al., Am. J. Respir. Crit. Care Med. 2003, 167(8):1109-12), upper gastrointestinal cancer (X. Chen, et al., Curr. CancerDrug Targets 2004, 4(3): 267-83; J. natl. cancer inst. 2003, 95(14):1053-61), and sepsis (H. Nakae, et al., Res. Commun. Chem. Pathol.Pharmacol. 1994, 83(2): 151-6, 84(3): 271-81), and skin burns.

Examples of textbooks on the subject of inflammation include: 1) Gallin,J. I.; Snyderman, R., Inflammation: Basic Principles and ClinicalCorrelates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999;2) Stvrtinova, V., et al., Inflammation and Fever. PathophysiologyPrinciples of Diseases (Textbook for Medical Students); Academic Press:New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B.Saunders Co., 1988; and 4) Stedman's Medical Dictionary.

Background and review material on inflammation and conditions relatedwith inflammation can be found in articles such as the following: C.Nathan, Points of control in inflammation, Nature 2002, 420: 846-852; K.J. Tracey, The inflammatory reflex, Nature 2002, 420: 853-859; L. M.Coussens and Z. Werb, Inflammation and cancer, Nature 2002, 420:860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420:868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease,Nature 2002, 420: 875-878; H. L. Weiner and D. J. Selkoe, Inflammationand therapeutic vaccination in CNS diseases, Nature 2002, 420: 879-884;J. Cohen, The immunopathogenesis of sepsis, Nature 2002, 420: 885-891;D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia andinflammation as partners in crime, Nature Medicine 2002, 8(11):1211-1217.

Inflammation is due to or associated with any one of a plurality ofconditions, such as asthma, chronic obstructed pulmonary disease (COPD),atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatorybowel diseases (including Crohn's disease and ulcerative colitis),psoriasis, atopic dermatitis, contact dermatitis, acne, myocardialinfarction, stroke, pain, itch (pruritus), gingivitis, uveitis,bronchitis, allergic rhinitis, cystic fibrosis, upper gastrointestinalcancer, sepsis, and skin burns, which are each characterized byexcessive or prolonged inflammation at some stage of the disease.

Aryl-substituted bridged or fused diamines are disclosed in U.S. PatentAppl. Publ. Nos. US2003/004191, US2005/043355, and US2006/074121 and inU.S. Pat. Nos. 6,559,140, 5,700,816, 5,585,492, 5,719,306, 6,506,876,5,723,492, and 6,407,140. Benzothiazole and benzoxazole LTA₄H modulatorshave been described in U.S. Patent Appl. Publ. Nos. US2005/0043378 andUS2005/0043379. In addition, diamine derivatives are described as LTA₄Hinhibitors in U.S. Patent Appl. Publ. Nos. 2007/0155726 and 2007/079078.However, there remains a need for potent LTA₄H modulators with desirablepharmaceutical properties. Certain aryl-substituted bridged or fuseddiamine derivatives have been found in the context of this invention tohave LTA₄H-modulating activity.

SUMMARY OF THE INVENTION

In one aspect the invention relates to chemical entities selected fromcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I), and pharmaceutically active metabolites of compounds ofFormula (I):

wherein

-   R¹ is H; —CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂-aryl substituted with    CO₂R^(a); —C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH;    —C(O)C(R^(a))(R^(b))—F; —C(O)C(R^(a))(R^(b))—CF₃;    —C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—N(R^(c))R^(d);    —C(O)N(R^(c))(R^(d)); —C(O)-cycloalkyl; —C(O)-(monocyclic    heteroaryl) optionally substituted with methyl; —C(O)-(monocyclic    heterocycloalkyl) optionally substituted with methyl or    —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl; —SO₂NH₂; —SO₂-cycloalkyl; or    —SO₂-(monocyclic heteroaryl) optionally substituted with methyl;    -   where R^(a) and R^(b) are each independently H or methyl; or        R^(a) and R^(b) taken together with the carbon to which they are        attached form a saturated monocyclic cycloalkyl or        heterocycloalkyl, optionally substituted with one or two methyl        groups;    -   R^(c) is H; and    -   R^(d) is H, C₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O)CF₃, or        —(CH₂)₀₋₁-monocyclic heteroaryl optionally substituted with one        or two methyl groups;-   X is N or >CHNR^(e)—;    -   where R^(e) is H or methyl;-   Z is N or >CHNR^(f)—;    -   where R^(f) is H or methyl; and    -   at least one of X and Z is N;-   m, n, p, and q are independently 0, 1, or 2 wherein the sum    (m+n+p+q) may not exceed 6; and provided that-   when the sum of m, n, p, and q is 2, then Y is a bond, —CH₂—, or    —CH₂CH₂—; and-   when the sum of m, n, p, and q is 4, 5 or 6, then Y is a bond;-   Q is O or CH₂, and said Q is linked at the “a” or “b” position of    the phenyl ring;-   D is O or S;-   R² is H, CH₃, OCH₃, halo, OH, NH₂, or CN;-   R³ is H or F; and-   A is —CH₂—, —CH₂CH₂—, or —OCH₂CH₂—.

In certain embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to pharmaceuticalcompositions each comprising an effective amount of at least onechemical entity selected from compounds of Formula (I), pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of Formula (I). Pharmaceutical compositions accordingto the invention may further comprise a pharmaceutically acceptableexcipient.

In another aspect, the chemical entities of the invention are useful asLTA₄H modulators. Thus, the invention is directed to a method formodulating LTA₄H activity, comprising exposing LTA₄H to an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).Embodiments of this invention inhibit LTA₄H activity.

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by LTA₄H activity, comprising administering to thesubject in need of such treatment an effective amount of at least onechemical entity selected from compounds of Formula (I), pharmaceuticallyacceptable salts of compounds of Formula (I), pharmaceuticallyacceptable prodrugs of compounds of Formula (I), and pharmaceuticallyactive metabolites of compounds of Formula (I).

In certain preferred embodiments of the inventive method, the disease,disorder, or medical condition is inflammation.

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a schematic representation of some features of theleukotriene synthesis pathway.

DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS

For the sake of brevity, the disclosures of the publications, includingpatents and patent applications, cited anywhere in this specificationare herein incorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted bya/symbol), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, unless otherwise indicated, the substitution is meantto occur at any valency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.Additionally, any formula given herein is intended to representhydrates, solvates, and polymorphs of such compounds, and mixturesthereof.

Certain formulae given herein are meso compounds, which are compoundsthat possess asymmetric centers (in this case, asymmetric carbons), butwhich are achiral molecules. Such compounds are named herein as mesocompounds. In some cases, meso compounds are depicted and named hereinwith a specific stereochemical configuration. However, one skilled inthe art will recognize the meso nature of such compounds. Examplesincludemeso-endo-(8-Methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-{2-[4-(6-methyl-benzothiazol-2-yloxy)-phenoxy]-ethyl}-amineandmeso-endo-3-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COON, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In still another example, an expressionsuch as “reacting an entity with a compound of formula R—COOH” refers tothe reacting of (a) such entity in the chemically relevant form, orforms, of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Inerest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²⁵I, respectively. Such isotopically labelled compounds areuseful in metabolic studies (preferably with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques[such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT)] including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or ¹¹C labeled compound may be particularly preferredfor PET or SPECT studies. Further, substitution with heavier isotopessuch as deuterium (i.e., ²H) may afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements. Isotopically labeledcompounds of this invention and prodrugs thereof can generally beprepared by carrying out the procedures disclosed in the schemes or inthe examples and preparations described below by substituting a readilyavailable isotopically labeled reagent for a non-isotopically labeledreagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻², A, D, Q, X, Y, Z, m, n, p, and q, and any other genericsubstituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻², A, D, Q, X, Y, Z, m, n, p, and q, and any other genericsubstituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B-, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the secondsubstituted member and B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

In some embodiments, R¹ is H; —CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂ arylsubstituted with CO₂R^(a); —C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH;—C(O)C(R^(a))(R^(b))—F; —C(O)C(R^(a))(R^(b))—CF₃;—C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—N(R^(c))R^(d);—C(O)N(R^(c))(R^(d)); —C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl)optionally substituted with methyl; —C(O)-(monocyclic heterocycloalkyl)optionally substituted with methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl;—SO₂NH₂; —SO₂-cycloalkyl; or —SO₂— (monocyclic heteroaryl) optionallysubstituted with methyl. In some embodiments, R^(a) and R^(b) are eachindependently H or methyl; or R^(a) and R^(b) taken together with thecarbon to which they are attached form a saturated monocyclic cycloalkylor heterocycloalkyl ring, optionally substituted with one or two methylgroups.

In some embodiments, R¹ is H; —CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂-arylsubstituted with CO₂R^(a); —C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH;—C(O)C(R^(a))(R^(b))—F; —C(O)C(R^(a))(R^(b))—CF₃;—C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—N(R^(c))R^(d);—C(O)NH₂; —C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl) optionallysubstituted with methyl; —C(O)-(monocyclic heterocycloalkyl) optionallysubstituted with methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl; —SO₂NH₂;—SO₂-cycloalkyl; or —SO₂— (monocyclic heteroaryl) optionally substitutedwith methyl. In some embodiments, R^(a) and R^(b) are each independentlyH or methyl; or R^(a) and R^(b) taken together with the carbon to whichthey are attached form a saturated monocyclic cycloalkyl.

In some embodiments, R¹ is H; —CH₂-aryl substituted with CO₂R^(a);—C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH; —C(O)C(R^(a))(R^(b))—F;—C(O)C(R^(a))(R^(b))—CF₃; —C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl;—C(O)C(R^(a))(R^(b))—N(R^(c))R^(d); —C(O)N(R^(c))(R^(d));—C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl) optionally substitutedwith methyl; —C(O)-(monocyclic heterocycloalkyl) optionally substitutedwith methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl; —SO₂NH₂; —SO₂-cycloalkyl;or —SO₂— (monocyclic heteroaryl) optionally substituted with methyl.

In some embodiments of Formula (I), R¹ is H, acetyl, 2-hydroxyacetyl,2-fluoro-acetyl, carboxymethyl, 3,3,3-trifluoro-propionyl,1-hydroxycyclopropane-carbonyl, 2-hydroxy-2-methyl-propionyl,tetrahydro-furan-3-carbonyl, tetrahydro-furan-2-carbonyl,tetrahydro-pyran-4-carbonyl, 2-tert-butoxycarbonylamino-acetyl,2-methoxy-acetyl, 2-amino-acetyl, carbamoyl, methanesulfonyl,tert-butoxycarbonylmethyl, 1H-pyrrole-2-carbonyl,1-methyl-1H-pyrrole-2-carbonyl, 1-methyl-1H-pyrrole-3-carbonyl,1-tert-butoxycarbonylamino-cyclopropanecarbonyl,1-tert-butoxycarbonyl-azetidine-3-carbonyl,2-(2,2,2-trifluoro-acetylamino)-acetyl, azetidine-3-carbonyl,cyclobutanecarbonyl, furan-2-carbonyl, furan-3-carbonyl,pyrazine-2-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl,cyclopropanecarbonyl, isoxazole-5-carbonyl, morpholine-4-carbonyl,sulfamoyl, pyridine-3-sulfonyl, furan-2-sulfonyl,1-methyl-1H-imidazole-2-sulfonyl, 1-methyl-1H-pyrrole-2-sulfonyl,thiophene-2-sulfonyl, thiophene-3-sulfonyl, cyclopropanesulfonyl,formamidyl, N-furan-2-ylmethyl-formamidyl, N-pyridin-4-yl-formamidyl,N-(3,5-dimethyl-isoxazol-4-yl)-formamidyl,

methoxycarbonylmethyl, ethoxycarbonylmethyl, or3-methoxycarbonyl-propyl.

In further embodiments, R¹ is acetyl or carbamoyl.

In some embodiments,

is 2,5-diaza-bicyclo[2.2.1]heptane, 8-aza-bicyclo[3.2.1]oct-3-ylamine,3,8-diaza-bicyclo[3.2.1]octane, octahydro-pyrrolo[3,4-b]pyrrole,octahydro-pyrrolo[3,4-c]pyrrole, octahydro-pyrrolo[3,4-c]pyridine,decahydro-[1,6]naphthyridine, or 3-Aza-bicyclo[3.1.0]hex-6-ylamine.

In further embodiments,

is (S,S)-2,5-diaza-bicyclo[2.2.1]heptane,(R,R)-2,5-diaza-bicyclo[2.2.1]heptane, orendo-3,8-aza-bicyclo[3.2.1]oct-3-yl-amine.

In some embodiments, A is —CH₂—, —CH₂CH₂—, or —OCH₂CH₂—.

In some embodiments, R³ is H. In other embodiments, R³ is fluoro.

In some embodiments, Q is O or CH₂ and is linked at the “a” or “b”position of the phenyl ring. In certain embodiments, Q is O and islinked to the a position. In certain embodiments, Q is O and is linkedto the b position. In certain embodiments, Q is CH₂ and is linked to thea position. In certain embodiments, Q is CH₂ and is linked to the bposition.

In some embodiments, D is O. In other embodiments, D is S.

In some embodiments, R² is H, CH₃, OCH₃, halo, OH, NH₂, or CN. Incertain embodiments, R₂ is H. In further embodiments R₂ is a halo. Infurther embodiments R₂ is CH₃.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove and of the specific compounds exemplified herein, and methodsusing such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methyl benzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as benzylamines, pyrrolidines, piperidine,morpholine, and piperazine, and inorganic salts derived from sodium,calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum,and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, ora polypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19,115. Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in J. Med.Chem. 1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

The present invention also relates to pharmaceutically activemetabolites of compounds of Formula (I), and uses of such metabolites inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997,40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites (collectively, “active agents”) of the present invention areuseful as LTA₄H modulators in the methods of the invention. Such methodsfor modulating LTA₄H activity comprise exposing LTA4H to an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).Embodiments of this invention inhibit LTA₄H activity.

In some embodiments, the LTA₄H is in a subject with a disease, disorder,or medical condition mediated by LTA₄H activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “medical conditions, disorders, or diseases.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated through LTA₄H activity, such asinflammation. Active agents according to the invention may therefore beused as anti-inflammatory agent(s).

In some embodiments, an active agent of the present invention isadministered to treat inflammation. Inflammation may be associated withvarious diseases, disorders, or conditions, such as inflammatorydisorders, allergic disorders, dermatological disorders, autoimmunedisease, lymphatic disorders, and immunodeficiency disorders, includingthe more specific conditions and diseases given below. Regarding theonset and evolution of inflammation, inflammatory diseases orinflammation-mediated diseases or conditions include, but are notlimited to, acute inflammation, allergic inflammation, and chronicinflammation.

Illustrative types of inflammation treatable with an LTA₄H modulatingagent include inflammation due to any one of a plurality of conditionssuch as allergy, asthma, nasal polyps, allergic rhinitis, nasal itch,ocular inflammation (e.g., post-surgical ocular inflammation),conjunctivitis, uveitis, dry eye, psoriasis, pruritus, itch, itchy skin,atopic dermatitis, urticaria (hives), contact dermatitis, scleroderma,skin burns, acne, inflammatory bowel diseases (including colitis,Crohn's disease and ulcerative colitis), chronic obstructed pulmonarydisease (COPD), atherosclerosis, arthritis (including rheumatoidarthritis), multiple sclerosis, myocardial infarction, stroke, pain,gingivitis, bronchitis, cystic fibrosis, upper gastrointestinal cancer,sepsis, autoimmune thyroid diseases, and immune-mediated (also known astype 1) diabetes mellitus and lupus, which are characterized byexcessive or prolonged inflammation at some stage of the disease. Otherautoimmune diseases that lead to inflammation include Myasthenia gravis,autoimmune neuropathies, such as Guillain-Barré, autoimmune uveitis,autoimmune hemolytic anemia, pernicious anemia, autoimmunethrombocytopenia, temporal arteritis, anti-phospholipid syndrome,vasculitides, such as Wegener's granulomatosis, Behcet's disease,dermatitis herpetiformis, pemphigus vulgaris, vitiligio, primary biliarycirrhosis, autoimmune hepatitis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland, polymyositis, dermatomyositis,spondyloarthropathies, such as ankylosing spondylitis, and Sjogren'ssyndrome.

Pruritis treatable with an LTA₄H-modulating agent according to theinvention includes that which is a symptom of allergic cutaneousdiseases (such as atopic dermatitis and hives) and other metabolicdisorders (such as chronic renal failure, hepatic cholestosis, anddiabetes mellitus).

In other embodiments, an active agent of the present invention isadministered to treat allergy, asthma, autoimmune diseases, pruritis,inflammatory bowel disease, ulcerative colitis, or cardiovasculardisease, including atherosclerosis and prevention of myocardialinfarction.

Thus, the active agents may be used to treat subjects diagnosed with orsuffering from a disease, disorder, or condition mediated through LTA₄Hactivity. The term “treat” or “treating” as used herein is intended torefer to administration of an active agent or composition of theinvention to a subject for the purpose of effecting a therapeutic orprophylactic benefit through modulation of LTA₄H activity. Treatingincludes reversing, ameliorating, alleviating, inhibiting the progressof, lessening the severity of, or preventing a disease, disorder, orcondition, or one or more symptoms of such disease, disorder orcondition mediated through modulation of LTA₄H activity. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human. “Modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize or down-regulate LTA₄H expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate LTA₄H expression or activity. Embodiments ofchemical entities according to this invention are LTA₄H-modulatingchemical entities.

In treatment methods according to the invention, an effective amount ofat least one active agent according to the invention is administered toa subject suffering from or diagnosed as having such a disease,disorder, or condition. An “effective amount” means an amount or dosesufficient to generally bring about the desired therapeutic orprophylactic benefit in patients in need of such treatment for thedesignated disease, disorder, or condition. When referring to modulatingthe target receptor, an “effective amount” means an amount sufficient toat least affect the activity of such receptor. Measuring the activity ofthe target receptor may be performed by routine analytical methods.Target receptor modulation is useful in a variety of settings, includingassays.

In addition, effective amounts or doses of the active agents of thepresent invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the agent, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An exemplary dose is in therange of from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from about 0.05 toabout 7 g/day, or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of Formula (I) orincluded with such an agent in a pharmaceutical composition according tothe invention. In an exemplary embodiment, additional active ingredientsare those that are known or discovered to be effective in the treatmentof conditions, disorders, or diseases mediated by LTA₄H activity, suchas another LTA₄H modulator or a compound active against another targetassociated with the particular condition, disorder, or disease. Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of anagent according to the invention), decrease one or more side effects, ordecrease the required dose of the active agent according to theinvention.

Other embodiments of this invention further comprise the administrationof at least one CysLT antagonist and/or at least one CysLT synthesisinhibitor. In some embodiments of this invention, such LTA₄H modulatorand CysLT antagonist and/or CysLT synthesis inhibitor arecoadministered. Examples of CysLT antagonists are CysLT1 and CysLT2antagonists.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises an effective amount of at leastone active agent in accordance with the invention. Such compositions mayfurther comprise a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., from about 0.05 to about 50mg/kg daily, or from about 0.05 to about 20 mg/kg daily, or from about0.1 to about 10 mg/kg daily.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient(s) may be mixed witha solid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

Exemplary chemical entities useful in methods of the invention will nowbe described by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to the most generic form of Formula (I).

Intermediates of formula A4, where Q is —CH₂— are prepared according toScheme A. Amines A1, where D is O or S, are condensed with phenylaceticacid compounds A2, with heating, to provide fused thiazoles or oxazolesA3. Where D is O, reactions are performed in the presence of anactivating agent such as carbonyldiimidazole. The free hydroxyl group isactivated using methods known in the art to give compounds A4, where LGis a suitable leaving group (such as chloro, bromo, iodo, tosyl, ormesyl). Preferably, thionyl chloride in CH₂Cl₂ is used to providecompounds A4 where LG is chloro. Analogs of A4 where Q is O are known inthe literature or are prepared according to methods described in U.S.Patent Appl. Publ. Nos. US2005/0043378 and US2005/0043379.

In one embodiment, compounds of Formula (I) where D is S are preparedaccording to Scheme B. Compounds A4, where D is S and LG is a suitableleaving group (such as halo, tosyl, or mesyl), are reacted with aminesB1 in the presence of a suitable base (such as Et₃N), in a polar solvent(such as acetonitrile) to give compounds of formula B2, where D is S.Amines B1, where R¹⁰ is R¹ or a suitable nitrogen protecting group, arecommercially available or are prepared using methods in the art ormethods described in EP 0266576 or WO 01/81347. Where R¹⁰ is R¹, oneskilled in the art will recognize compounds B2 are embodiments ofFormula (I).

Compounds of formula B2, where D is S, are also prepared by reductiveamination protocols. Aldehydes C1, where D is S and R is —CHO or—CH₂CHO, are commercially available or are prepared using methods in theart or methods described in U.S. Patent Appl. Publ. Nos. US2005/0043378and US2005/0043379. Aldehydes C1 may also be used or purified in aprotected form, such as a bisulfite complex. Reaction of aldehydes C1with amines B1 in the presence of a suitable reducing agent (such asNaCNBH₃ or NaB(OAc)₃H) in a solvent such as 1,2-dichloroethane (DCE),CH₂Cl₂, methanol, or ethanol, and optionally employing an acid catalyst(such as acetic acid or ZnCl₂) provides compounds B2, where D is S.

Alternatively, phenols D1 (prepared using methods analogous to those inthe preceding reaction schemes) are reacted with chlorides D2 (where Dis S or O) to form compounds B2 where D is S. Compounds of formula D2are commercially available or are prepared using methods in the art ormethods described in Intl. Pat. Appl. No. WO 2006/04475 and L. Zhu, etal. J. Heterocyclic Chem. 2005, 42, 727-730.

Compounds B2, where D is S or O and R¹⁰ is a suitable protecting group(such as tert-butylcarbamoyl group), are converted to compounds ofFormula (I) according to Scheme E. Where R¹⁰ is a suitable protectinggroup, deprotection is effected using generally known methods. Forexample, where R¹⁰ is a Boc group, deprotection is accomplished using anacid such as HCl or TFA, in a solvent such as Et₂O, dioxane, or CH₂Cl₂.Substituents R¹ are installed by acylation, sulfonylation, reductiveamination, or alkylation protocols using methods known in the art togive compounds of Formula (I).

Compounds of Formula (I) may be converted to their corresponding saltsusing methods described in the art. For example, an amine of Formula (I)is treated with trifluoroacetic acid, HCl, or citric acid in a solventsuch as Et₂O, CH₂Cl₂, THF, or MeOH to provide the corresponding saltform.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES Chemistry Methods

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt). Where solutions were “dried,” they were generallydried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures,solutions, and extracts were “concentrated”, they were typicallyconcentrated on a rotary evaporator under reduced pressure.

Analytical reversed-phase HPLC was performed on an Agilent 1100 Seriesinstrument using one of the following gradients: 1 to 99%acetonitrile/water (0.05% trifluoroacetic acid) over 5.0 min or 7.0 minwith a flow rate of 1 mL/min (Waters XTerra MS C18 (5 μm, 4.6×100 mm)column or Phenomenex Synergi max-RP (4 μm, 4.6×150 mm) column) or 1 to99% acetonitrile/water (20 mM NH₄OH) over 5.0 min or 7.0 min with a flowrate of 1.5 mL/min (Phenomenex Gemeni C18 (5 μm, 3.0×150 mm) column).Analytical reversed phase LC/MS was performed either on an Agilent 1100Series instrument using 5 to 99% acetonitrile/water (0.05%trifluoroacetic acid) over 5.0 min or 7.0 min with a flow rate of 0.6mL/min (Waters XTerra RP18 (5 μm, 3.0×100 mm) column) or on a Waters2790 instrument using 5 to 99% acetonitrile/water (0.1% formic acid)over 5.0 min with a flow rate of 0.6 mL/min (Waters XTerra RP18 (5 μm,3.0×100 mm) column).

Preparative reversed phase HPLC was performed on a Dionex APS2000 LC/MSor HPLC with a Phenomenex Gemini C18 (5 μm, 30×100 mm) column or aWaters XBridge C18 (5 μm, 30×100 mm) column and variable gradients ofacetonitrile/water (20 mM NH₄OH) at a flow rate of 30 mL/min.Alternatively, the purification was performed with a Phenomenex GeminiC18 (5 μm, 50×100 mm) column or a Waters XBridge C18 (5 μm, 50×100 mm)column and variable gradients of acetonitrile/water (20 mM NH₄OH) at aflow rate of 80 mL/min.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration). NMR interpretation wasperformed using MestReC or MestReNova software to assign chemical shiftand multiplicity. In cases where 2 adjacent peaks of equal or unequalheight were observed, these 2 peaks may be labeled either as a multipletor as a doublet. In the case of a doublet a coupling constant using thissoftware may be assigned. In any given example, one or more protons maynot be reported due to obscurity by water and/or solvent peaks.

Chemical names were typically generated using ChemDraw Version 6.0.2(CambridgeSoft, Cambridge, Mass.) or ACD/Name Version 9 (AdvancedChemistry Development, Toronto, Ontario, Canada).

Example 1(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

Step A:(S,S)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. To a stirred solution of2-(4-chloromethyl-phenoxy)-benzothiazole (15.3 g, 55.3 mmol) and(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(13.2 g, 66.4 mmol) in CH₃CN (200 mL) was added triethylamine (Et₃N)(11.5 mL, 82.9 mmol). The resulting solution was stirred at rt for 24 hand then concentrated. The crude residue was then partitioned betweenCH₂Cl₂ (800 mL) and saturated (satd.) aqueous (aq.) NaHCO₃ (200 mL). Theorganic layer was separated, dried (Na₂SO₄), filtered and concentrated.Purification by silica gel flash chromatography (10% to 40% ethylacetate (EtOAc) in hexanes) afforded the title compound as a white foam(17.2 g, 71%). MS (ESI): mass calcd. for C₂₄H₂₇N₃O₃S, 437.18; m/z found,438.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d,J=7.1 Hz, 1H), 7.66 (d, J=7.1 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.38 (m,1H), 7.32-7.24 (br m, 3H), 4.40 (br m, 0.5H), 4.26 (br m, 0.5H), 3.76(br d, J=9.7 Hz, 2H), 3.63 (br d, J=10.5 Hz, 0.5H), 3.50 (br m, 1H),3.46 (m, 0.5H), 3.18 (br m, 1H), 2.93 (br d, J=8.8 Hz, 0.5H), 2.88 (brd, J=9.4 Hz, 0.5H), 2.73 (br d, J=9.2 Hz, 0.5H), 2.55 (br d, J=9.2 Hz,0.5H), 1.87 (br t, J=8.8 Hz, 1H), 1.74 (br d, J=9.3 Hz, 0.5H), 1.68 (brd, J=9.3 Hz, 0.5H), 1.47 (s, 9H).

Step B:(S,S)-2-[4-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride. To a stirred solution of(S,S)-5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (8.2 g, 18.7 mmol) in CH₂Cl₂ (200 mL) was addedHCl (4.0 N in 1,4-dioxane, 46 mL, 187 mmol). The resulting whitesuspension was stirred at rt for 4 h and then concentrated affording thetitle compound as a white solid (5.4 g, 70%). MS (ESI): mass calcd. forC₁₉H₁₉N₃OS, 337.12; m/z found, 338.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):7.84 (m, 3H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (m, 2H), 7.44 (m, 1H), 7.34(m, 1H), 4.67 (br m, 3H), 4.55 (br m, 1H), 4.05 (br m, 1H), 3.84 (br d,J=13.2 Hz, 1H), 3.60 (dd, J=13.7, 2.7 Hz, 3H), 2.79 (br m, 1H), 2.34 (brd, J=12.7 Hz, 1H).

Step C:(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone.To a stirred solution of(S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride (109 mg, 0.27 mmol) and Et₃N (150 μL, 1.1 mmol) in CH₂Cl₂(4 mL) was added acetic anhydride (40 μL, 0.4 mmol), and the resultingsolution was then stirred at rt for 18 h. The resulting white suspensionwas partitioned between CH₂Cl₂ (150 mL) and satd. aq. NaHCO₃ (50 mL).The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated. Purification by silica gel flash chromatography (0% to 5%CH₃OH in CH₂Cl₂) afforded the title compound as a viscous, colorless oil(93 mg, 92%). MS (ESI): mass calcd. for C₂₁H₂₁N₃O₂S, 379.14; m/z found,380.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d,J=7.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.33-7.24 (m,3H), 4.78 (br m, 0.5H), 4.23 (m, 0.5H), 3.78-3.73 (br m, 2.5H), 3.56 (m,1.5H), 3.32 (dd, J=9.3, 2.2 Hz, 0.5H), 3.27 (dd, J=11.4, 2.3 Hz, 0.5H),3.01 (dd, J=9.1, 2.2 Hz, 0.5H), 2.84 (dd, J=9.7, 2.1 Hz, 0.5H), 2.77 (brd, J=9.9 Hz, 0.5H), 2.56 (dd, J=9.9, 1.2 Hz, 0.5H), 2.08 (s, 1.5H), 2.00(s, 1.5H), 1.98 (br m, 0.5H), 1.91 (br m, 0.5H), 1.80 (br m, 0.5H), 1.66(br m, 0.5H).

Example 2(S,S)-1-{5-[3-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

This compound was prepared using the methods outlined in Example 1,substituting the appropriate chloromethyl phenoxy-benzothiazole. MS(ESI): mass calcd. for C₂₁H₂₁N₃O₂S, 379.14; m/z found, 380.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.1 Hz, 1H), 7.67(m, 1H), 7.42-7.36 (m, 3H), 7.30-7.23 (m, 3H), 4.77 (br m, 0.5H), 4.22(m, 0.5H), 3.80 (br m, 1H), 3.77 (s, 1H), 3.74 (dd, J=11.5, 2.2 Hz,0.5H), 3.56 (m, 1.5H), 3.31 (dd, J=9.4, 2.1 Hz, 0.5H), 3.26 (dd, J=11.5,2.2 Hz, 0.5H), 3.03 (dd, J=9.4, 2.2 Hz, 0.5H), 2.83 (dd, J=9.8, 2.2 Hz,0.5H), 2.76 (br d, J=10.3 Hz, 0.5H), 2.55 (dd, J=9.8, 1.2 Hz, 0.5H),2.07 (s, 1.5H), 1.98 (s, 1.5H), 1.97 (br m, 0.5H), 1.89 (br m, 0.5H),1.79 (br m, 0.5H), 1.65 (br m, 0.5H).

Example 3(R,R)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

Step A:(4S,2R)-4-Methanesulfonyloxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester. To a solution of4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(10.85 g, 50.0 mmol) in pyridine (50 mL) was added methanesulfonylchloride (10.8 mL, 140 mmol) over a period of 20 min. After stirring for16 h, the reaction mixture was concentrated to dryness, diluted withsatd. aq. Na₂CO₃ and extracted with EtOAc (2×). The combined organiclayers were dried (MgSO₄), filtered and concentrated to provide thetitle compound as an oil that slowly solidified (14.4 g, 84%). ¹H NMR(400 MHz, CDCl₃): 5.24-5.20 (m, 1H), 4.72-4.47 (m, 1H), 4.32-4.17 (m,2H), 4.01-3.75 (m, 1H), 3.63-3.48 (m, 1H), 3.04 (s, 3H), 3.01 (s, 3H),2.60-2.25 (m, 2H), 1.48 (s, 9H).

Step B: (2R,5R)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester. A heterogeneous mixture of(4S,2R)-4-methanesulfonyloxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2.7 mmol) in ammonium hydroxide (27 wt %solution in water, 10 mL) was warmed to 65° C. in a sealed tube for 16 hduring which time the mixture became homogeneous. The aqueous wasextracted with CH₂Cl₂ (2×) and the combined organics were dried overNa₂SO₄, filtered, and concentrated to provide the title compound as ayellow solid that was used directly in subsequent steps (350 mg, 66%).MS (ESI): mass calcd. for C₁₀H₁₈N₂O₂, 198.1; m/z found, 199.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 4.48-4.27 (m, 1H), 3.70 (s, 1H), 3.41-3.30 (m,1H), 3.22-3.11 (m, 1H), 3.08-2.95 (m, 2H), 1.80-1.65 (m, 2H), 1.48 (s,9H).

Step C. The title compound was prepared using the methods analogous tothose outlined in Example 1, Steps B and C. MS (ESI): mass calcd. forC₂₁H₂₁N₃O₂S, 379.14; m/z found, 380.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃,mixture of rotamers): 7.76-7.72 (m, 1H), 7.69-7.66 (m, 1H), 7.45-7.36(m, 3H), 7.34-7.25 (m, 3H), 4.79 (br s, 0.5H), 4.24 (br s, 0.5H),3.80-3.72 (m, 2.5H), 3.60-3.54 (m, 1.5H), 3.33 (dd, J=9.3, 2.3 Hz,0.5H), 3.28 (dd, J=11.4, 2.0 Hz, 0.5H), 3.02 (dd, J=11.4, 2.0 Hz, 0.5H),2.87-2.75 (m, 1H), 2.56 (dd, J=9.5, 1.1 Hz, 0.5H), 2.09 (s, 1.5H), 2.01(s, 1.5H), 2.01-1.64 (m, 2H).

Example 4(S,S)-1-[5-(4-Benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone

Step A: (4-Benzothiazol-2-ylmethyl-phenyl)-methanol. To(4-hydroxymethyl-phenyl)-acetic acid (2 g, 12 mmol) was added2-amino-benzenethiol (13.2 g, 12 mmol) and the mixture was heated at160° C. for 48 h. The crude residue was then partitioned between EtOAc(200 mL) and 1 N NaOH (200 mL). The organic layer was separated, washedwith satd. aq. NaCl (200 mL), dried (MgSO₄), filtered and concentrated.Purification by silica gel flash chromatography (0% to 80% EtOAc inhexanes) afforded the title compound as a colorless oil (0.42 g, 14%).MS (ESI): mass calcd. for C₁₅H₁₃NOS, 255.34; m/z found, 456.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 8.00 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H),7.48-7.45 (m, 1H), 7.39-7.28 (m, 5H), 4.71 (s, 2H), 4.44 (s, 2H).

Step B: 2-(4-Chloromethyl-benzyl)-benzothiazole. To a solution of(4-benzothiazol-2-ylmethyl-phenyl)-methanol (2.1 g, 8.1 mmol) in CH₂Cl₂(90 mL) was added thionyl chloride (0.65 mL, 8.9 mmol) and the mixturewas stirred at rt for 4 h. The reaction mixture was concentrated toafford the title compound as a tan solid (2.6 g, 100%). MS (ESI): masscalcd. for C₁₅H₁₂ClNS, 273.04; m/z found, 274.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.34 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.71-7.67 (m,1H), 7.61-7.58 (m, 1H), 7.50-7.48 (m, 2H), 7.45-7.44 (m, 2H), 4.84 (s,2H), 4.60 (s, 2H).

Step C:5-(4-Benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. To a solution of2-(4-chloromethyl-benzyl)-benzothiazole (1.0 g, 3.7 mmol) and(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(0.9 g, 4.4 mmol) in CH₃CN (36 mL) was added Et₃N (0.77 mL, 5.5 mmol)and the resulting solution was stirred at rt for 24 h. The reactionmixture was then concentrated and the crude residue was then partitionedbetween CH₂Cl₂ (200 mL) and satd. aq. NaHCO₃ (200 mL). The organic layerwas separated, dried (MgSO₄), filtered and concentrated. Purification bysilica gel flash chromatography (0% to 10% CH₃OH in CH₂Cl₂) afforded thetitle compound as clear oil (0.88 g, 55%). MS (ESI): mass calcd. forC₂₅H₂₉N₃O₂S, 435.59; m/z found, 436.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃,mixture of rotamers): 8.01 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H),7.48-7.45 (m, 1H), 7.37-7.34 (m, 5H), 4.44 (s, 2H), 4.40 (br s, 0.5H),4.25 (br s, 0.5H), 3.75-3.75 (m, 2H), 3.64-3.44 (m, 2H), 3.17 (t, J=11.3Hz, 1H), 2.90 (dd, J=25.2, 9.5 Hz, 1H), 2.74 (d, J=9.6 Hz, 0.5H), 2.55(d, J=9.4 Hz, 0.5H), 1.88-1.86 (br m, 1H), 1.73-1.65 (br m, 1H), 1.48(s, 9H).

Step D:(S,S)-2-[4-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzyl]-benzothiazoledihydrochloride. To a solution of5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.82 g, 1.9 mmol) in CH₂Cl₂ (19 mL) was added HCl(4.0 N in 1,4-dioxane, 7 mL) and the resulting white suspension wasstirred at rt for 4 h. The reaction mixture was concentrated affordingthe title compound as a white solid (0.9 g, 100%). MS (ESI): mass calcd.for free amine C₂₀H₂₁N₃S, 335.47; m/z found, 336.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): 12.09-11.07 (br m, 1H), 10.16-9.71 (br m, 2H), 8.03 (d,J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72-7.70 (m, 2H), 7.50-7.47 (m,3H), 7.42-7.39 (m, 1H), 4.62-4.59 (br m, 0.5H), 4.52 (br s, 2H),4.48-4.44 (br m, 2H), 4.37-4.34 (br m, 1.5H), 3.95-3.92 (m, 1H),3.72-3.70 (m, 1H), 3.34-3.30 (m, 2H), 2.69-2.63 (m, 0.5H), 2.48-2.43 (m,0.5H), 2.13-2.06 (m, 1H).

Step E:(S,S)-1-[5-(4-Benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone.This compound was prepared using methods analogous to those outlined inExample 1, Step C. MS (ESI): mass calcd. for C₂₂H₂₃N₃OS, 377.51; m/zfound, 378.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 8.01(d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.33(m, 5H), 4.78 (br s, 0.5H), 4.44 (d, J=2.0 Hz, 2H), 4.22 (br s, 0.5H),3.76-3.73 (m, 2.5H), 3.58-3.53 (m, 1.5H), 3.31-3.25 (m, 1H), 3.00 (dd,J=9.8, 2.3 Hz, 0.5H), 2.84 (dd, J=9.8, 2.3 Hz, 0.5H), 2.78-2.76 (br m,0.5H), 2.57-2.55 (br m, 0.5H), 2.08 (s, 1.5H), 2.00 (s, 1H), 1.99-1.97(m, 1H), 1.91-1.89 (br d, 0.5H), 1.80-1.78 (br d, 0.5H), 1.66-1.64 (m,0.5H).

Example 5meso-endo-N-[8-(4-Benzothiazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-acetamide

This compound was prepared using methods analogous to those outlined inExample 4. MS (ESI): mass calcd. for C₂₄H₂₇N₃OS, 405.57; m/z found,406.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.99 (d, J=7.7 Hz, 1H), 7.79 (d,J=7.7 Hz, 1H), 7.54 (dt, J=7.8, 1.2 Hz, 1H), 7.36-7.30 (m, 6H), 5.81 (brd, J=6.8 Hz, 1H), 4.42 (s, 2H), 4.10 (dd, J=14.2, 7.0 Hz, 1H), 3.52-3.51(br m, 2H), 3.18 (br s, 2H), 2.23-2.12 (br m, 3H), 1.96 (s, 3H),1.76-1.70 (br m, 2H), 1.58 (br d, J=14.4 Hz, 2H).

Example 6meso-endo-N-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-acetamide

Step A: (4-Benzooxazol-2-ylmethyl-phenyl)-methanol. A mixture of(4-hydroxymethyl-phenyl)-acetic acid (5.0 g, 30.1 mmol) and2-amino-phenol (6.6 g, 60.2 mmol) was heated at 180° C. for 3 h. Thecrude residue was cooled and then dissolved in THF (50 mL). Theresulting solution was treated with carbonyldiimidazole (3.7 g, 22.5mmol) and stirred at 80° C. for 72 h. The reaction mixture was thenpartitioned between EtOAc (200 mL) and water (200 mL). The organic layerwas dried (MgSO₄), filtered and concentrated. Purification by silica gelflash chromatography (0% to 80% EtOAc in hexanes) followed by a secondsilica gel flash chromatography (0% to 10% CH₃OH in CH₂Cl₂) afforded acolorless oil. The crude oil was then partitioned between EtOAc (200 mL)and 1 N NaOH (200 mL). The organic layer was dried (MgSO₄), filtered andconcentrated to afford the title compound as a colorless oil (1.5 g,20%). MS (ESI): mass calcd. for C₁₅H₁₃NO₂, 239.09; m/z found, 240.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.70-7.68 (m, 1H), 7.49-7.46 (m, 1H),7.40-7.35 (m, 4H), 7.33-7.29 (m, 2H), 4.69 (br d, J=4.5 Hz, 2H), 4.28(s, 2H).

Step B: 2-(4-Chloromethyl-benzyl)-benzooxazole. This compound wasprepared using the methods outlined in Example 4, Step B, substituting(4-benzooxazol-2-ylmethyl-phenyl)-methanol for(4-benzothiazol-2-ylmethyl-phenyl)-methanol. MS (ESI): mass calcd. forC₁₅H₁₂ClNO, 257.06; m/z found, 258.1 [M+H]⁺.

Step C.meso-endo-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-carbamicacid tert-butyl ester. This compound was prepared using the methodsoutlined in Example 4, Step C, substituting2-(4-chloromethyl-benzyl)-benzooxazole for2-(4-chloromethyl-benzyl)-benzothiazole. MS (ESI): mass calcd. forC₂₇H₃₃N₃O, 447.25; m/z found, 448.3 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.71-7.69 (m, 1H), 7.49-7.47 (m, 1H), 7.37-7.30 (m, 6H), 4.85 (br s,1H), 4.27 (s, 2H), 3.82 (br s, 1H), 3.51 (s, 2H), 3.17 (br s, 2H),2.20-2.10 (m, 4H), 1.81-1.79 (br m, 2H), 1.62-1.45 (br m, 2H), 1.45 (s,9H).

Step D:meso-endo-8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-ylaminedihydrochloride. This compound was prepared using the methods outlinedin Example 4, Step D, substitutingmeso-endo-[8-(4-benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-carbamicacid tert-butyl ester for5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. MS (ESI): mass calcd. for free amine C₂₂H₂₅N₃O,347.20; m/z found, 348.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 11.11 (br s,1H), 8.36 (br s, 3H), 7.78-7.66 (m, 4H), 7.46 (d, J=8.0 Hz, 2H),7.38-7.33 (m, 2H), 4.39 (s, 2H), 4.14 (br d, J=6.5 Hz, 2H), 3.75 (br s,2H), 3.48-3.43 (m, 1H), 2.75-2.72 (m, 2H), 2.39-2.37 (m, 2H), 2.23-2.20(m, 2H), 2.03 (br d, J=16.0 Hz, 2H).

Step E:meso-endo-N-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-acetamide.This compound was prepared using methods analogous to those outlined inExample 4, Step E. MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂, 389.50; m/zfound, 390.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.70-7.68 (m, 1H),7.48-7.46 (m, 1H), 7.36-7.27 (m, 6H), 5.80 (br d, J=6.0 Hz, 1H), 4.26(s, 2H), 4.10 (dd, J=7.2, 6.8 Hz, 1H), 3.49 (s, 2H), 3.17 (br s, 2H),2.22-2.11 (m, 4H), 1.96 (s, 3H), 1.76-1.71 (m, 2H), 1.57 (br d, J=14.0Hz, 2H).

Example 7(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

Step A:(S,S)-5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. To a stirred solution of2-[4-(2-bromo-ethyl)-phenoxy]-benzothiazole (1.5 g, 4.5 mmol) and(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(980 mg, 4.9 mmol) in CH₃CN (20 mL) at rt was added Et₃N (900 μL, 6.3mmol). The resulting suspension was stirred at rt for 24 h and thenpartitioned between CH₂Cl₂ (200 mL) and satd. aq. NaHCO₃ (80 mL). Theorganic layer was separated, dried (Na₂SO₄), filtered and concentrated.Purification by silica gel flash chromatography (EtOAc) afforded thetitle compound as a white foam (1.1 g, 56%). MS (ESI): mass calcd. forC₂₅H₂₉N₃O₃S, 451.19; m/z found, 452.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃,mixture of rotamers): 7.73 (d, J=8.4 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H),7.38 (m, 1H), 7.30-7.24 (m, 5H), 4.38 (br m, 0.5H), 4.24 (br m, 0.5H),3.53 (br m, 2H), 3.16 (t, J=10.4 Hz, 1H), 3.03 (d, J=8.4 Hz, 0.5H), 2.98(d, J=9.8 Hz, 0.5H), 2.86-2.74 (br m, 4H), 2.69 (br d, J=9.8 Hz, 0.5H),2.52 (br d, J=9.4 Hz, 0.5H), 1.84 (br d, J=9.2 Hz, 1H), 1.73 (br d,J=10.0 Hz, 0.5H), 1.69 (br d, J=9.2 Hz, 0.5H), 1.46 (s, 9H).

Step B (Example 7B):(S,S)-2-{4-[2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazolehydrochloride. This compound was prepared using the methods outlined inExample 1, Step B, substituting(S,S)-5-{2-[4-(benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester for(S,S)-5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. MS (ESI): mass calcd. for C₂₀H₂₁N₃OS, 351.14; m/zfound, 352.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.80 (d, J=6.5 Hz, 1H),7.65 (d, J=7.7 Hz, 1H), 7.52 (br d, J=8.3 Hz, 2H), 7.47-7.37 (m, 3H),7.33 (m, 1H), 4.73 (br m, 1H), 4.65 (br m, 1H), 3.98 (dd, J=13.9, 2.2Hz, 1H), 3.80-3.45 (br m, 6H), 3.23 (br m, 2H), 2.67 (br m, 1H), 2.33(br m, 1H).

Step C:(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone.This compound was prepared using methods analogous to those outlined inExample 1, Step C. MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.15; m/zfound, 394.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73(d, J=8.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 7.31-7.24 (m,5H), 4.76 (br m, 0.5H), 4.22 (br m, 0.5H), 3.69 (dd, J=11.5, 2.2 Hz,0.5H), 3.61 (m, 1H), 3.56 (dd, J=11.4, 2.2 Hz, 0.5H), 3.31 (dd, J=9.4,2.2 Hz, 0.5H), 3.26 (dd, J=11.5, 2.2 Hz, 0.5H), 3.12 (dd, J=9.8, 2.1 Hz,0.5H), 2.95 (dd, J=10.0, 2.2 Hz, 0.5H), 2.87-2.75 (br m, 4H), 2.72 (d,J=9.4 Hz, 0.5H), 2.54 (dd, J=9.3, 2.1 Hz, 0.5H), 2.09 (s, 1.5H), 1.98(s, 1.5H), 1.96 (br m, 0.5H), 1.89 (br m, 0.5H), 1.80 (br m, 0.5H), 1.68(br m, 0.5H).

Example 8(S,S)-1-(5-{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

This compound was prepared using the methods outlined in Example 7,substituting the appropriate bromoethyl phenoxy-benzothiazole. MS (ESI):mass calcd. for C₂₃H₂₃N₃O₃S, 393.15; m/z found, 394.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.4 Hz, 1H), 7.67 (d,J=7.1 Hz, 1H), 7.42-7.33 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.18 (br m,2H), 7.13 (br d, J=7.3 Hz, 1H), 4.75 (br s, 0.6H), 4.20 (br s, 0.4H),3.66 (br d, J=13.0 Hz, 0.4H), 3.58 (br s, 1H), 3.53 (br d, J=9.4 Hz,0.6H), 3.29 (dd, J=9.4, 2.2 Hz, 0.6H), 3.24 (dd, J=11.5, 2.1 Hz, 0.4H),3.09 (dd, J=9.4, 2.2 Hz, 0.4H), 2.92 (dd, J=9.6, 2.2 Hz, 0.6H),2.88-2.75 (br m, 4H), 2.70 (br d, J=9.9 Hz, 0.6H), 2.53 (br d, J=9.2 Hz,0.4H), 2.07 (s, 1H), 1.95 (s, 2H), 1.92 (br d, J=10.6 Hz, 0.4H), 1.85(br d, J=9.9 Hz, 0.6H), 1.77 (br d, J=9.9 Hz, 0.4H), 1.65 (br d, J=9.9Hz, 0.6H).

Example 9(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

Step A:(S,S)-5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester. To a stirred solution of2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (1.5 g, 4.3 mmol) and(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(1.0 g, 5.1 mmol) in CH₃CN (20 mL) at rt was added diisopropylethylamine((i-Pr)₂NEt) (900 μL, 5.1 mmol). The resulting suspension was stirred atrt for 4 h and then heated for 65 h at 60° C. The solution was cooled tort and then partitioned between CH₂Cl₂ (200 mL) and satd. aq. NaHCO₃ (80mL). The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated. Purification by silica gel flash chromatography (0% to 5%CH₃OH in CH₂Cl₂) afforded the title compound as a yellow oil (1.8 g,92%). MS (ESI): mass calcd. for C₂₅H₂₉N₃O₄S, 467.19; m/z found, 468.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.75 (d, J=8.0 Hz, 1H), 7.68-7.66 (m,1H), 7.42-7.38 (m, 1H), 7.31-7.25 (m, 3H), 6.99-6.95 (m, 2H), 4.40 (brs, 0.5H), 4.27 (br s, 0.5H), 4.13-4.03 (m, 2H), 3.66-3.51 (m, 2H),3.26-2.97 (m, 4H), 2.78 (d, J=9.5 Hz, 0.5H), 2.63 (d, J=9.7 Hz, 0.5H),1.92-1.85 (m, 1H), 1.79-1.70 (m, 1H), 1.49 (s, 9H).

Step B:(S,S)-2-{4-[2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazoletrifluoroacetate. To a stirred solution of(S,S)-5-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (1.7 g, 3.6 mmol) in CH₂Cl₂ (15 mL) was addedtrifluoroacetic acid (5 mL, 65 mmol). The resulting solution was stirredat rt for 8.5 h. The solution was concentrated to provide the titlecompound as an oil and used as a crude compound. MS (ESI): mass calcd.for C₂₀H₂₁N₃O₂S, 367.14; m/z found, 368.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃, mixture of rotamers): 7.73 (d, J=7.9 Hz, 1H), 7.65 (d, J=7.9 Hz,1H), 7.38 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 3H), 6.99-6.91 (m, 2H),4.13-4.01 (m, 2H), 3.56-3.39 (m, 2H), 3.35-3.32 (m, 1H), 3.20 (d, J=10.4Hz, 0.5H), 3.09 (dd, J=9.7, 2.4 Hz, 0.5H), 3.06-2.82 (m, 3.5H),2.76-2.67 (m, 1H), 2.50 (dd, J=9.6, 1.1 Hz, 0.5H), 1.88-1.57 (m, 2H).

Step C:(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone.This compound was prepared using methods analogous to those outlined inExample 1, Step C. MS (ESI): mass calcd. for C₂₂H₂₃N₃O₃S, 409.15; m/zfound, 410.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73(d, J=8.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.2 Hz, 0.25H),7.38 (s, 0.5H), 7.36 (d, J=1.2 Hz, 0.25H), 7.30-7.24 (m, 3H), 6.97-6.93(m, 2H), 4.77 (s, 0.5H), 4.23 (s, 0.5H), 4.11-4.02 (m, 2H), 3.75-3.68(m, 1.5H), 3.61 (dd, J=9.5, 1.2 Hz, 0.5H), 3.32 (ddd, J=13.5, 10.5, 2.1Hz, 1H), 3.21 (dd, J=9.6, 2.1 Hz, 0.5H), 3.06-2.94 (m, 2.75H), 2.81 (dd,J=9.7, 0.9 Hz, 0.5H), 2.65 (dd, J=9.6, 1.3 Hz, 0.5H), 2.10 (s, 1.25H),2.00 (s, 1.75H), 1.97 (s, 0.25H), 1.90 (d, J=10.0 Hz, 0.5H), 1.81 (d,J=9.7 Hz, 0.5H), 1.70 (d, J=9.9 Hz, 0.5H).

Example 10(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone

To a stirred suspension of(S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride (1.6 g, 3.9 mmol), glycolic acid (600 mg, 7.8 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 7.8mmol) in CH₂Cl₂ (15 mL) was added Et₃N (2.7 mL, 19.5 mmol). Theresulting solution was then stirred at rt for 16 h. The resulting whitesuspension was partitioned between CH₂Cl₂ (600 mL) and satd. aq. NaHCO₃(100 mL). The organic layer was separated, dried (Na₂SO₄), filtered andconcentrated. Purification by silica gel flash chromatography (0% to 5%CH₃OH in CH₂Cl₂) afforded the title compound as a white solid (853 mg,55%). MS (ESI): mass calcd. for C₂₁H₂₁N₃O₃S, 395.13; m/z found, 396.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.5 Hz,1H), 7.67 (d, J=8.0 Hz, 1H), 7.41 (m, 2H), 7.38 (m, 1H), 7.32 (br m,2H), 7.28 (m, 1H), 4.83 (br m, 0.5H), 4.21 (br d, J=14.5 Hz, 0.5H),4.10-3.99 (br m, 2H), 3.80 (br d, J=11.7 Hz, 0.5H), 3.76 (d, J=13.8 Hz,2H), 3.61 (br s, 1H), 3.50 (br s, 0.5H), 3.48-3.45 (m, 0.5H), 3.42 (brs, 0.5H), 3.39-3.35 (m, 0.5H), 3.23 (dd, J=9.2, 2.3 Hz, 0.5H), 3.01 (dd,J=9.7, 2.1 Hz, 0.5H), 2.90 (dd, J=9.8, 2.2 Hz, 0.5H), 2.81-2.77 (m,0.5H), 2.58 (dd, J=9.7, 1.2 Hz, 0.5H), 2.07-2.01 (m, 0.5H), 2.00-1.96(m, 0.5H), 1.80 (d, J=9.8 Hz, 0.5H), 1.70 (d, J=10.0 Hz, 0.5H).

Alternative Preparation:

Step A:5-(2-Acetoxy-acetyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester. A solution of (S,S)-Boc-[2.2.1]diazobicycloheptane(150.6 g, 0.76 mol) in CH₂Cl₂ (1.5 L) was cooled to 5° C. and Et₃N (117mL, 0.84 mol) was added. Over 50 min was then added acetoxy acetylchloride (82 mL, 0.76 mol). The ice bath was removed and theheterogeneous mixture was stirred for 16 h. The reaction mixture wasthen poured over 9 wt % NaHCO_(3(aq)) solution (1.5 L) and the layerswere mixed and separated. The organic layer was washed with 26 wt %NaCl_((aq)) (1.5 L), dried (Na₂SO₄), filtered, and concentrated toprovide the title compound as a white solid (217 g, 96%). ¹H NMR (600MHz, DMSO-d₆, 100° C.): 4.75-4.41 (m, 4H), 3.50-3.46 (m, 4H), 2.86 (s,2H), 2.04 (s, 3H), 1.85-1.72 (m, 2H), 1.41 (s, 9H).

Step B: 1-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanonehydrochloride. To a slurry of5-(2-acetoxy-acetyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester (1.2 g, 4 mmol) in isopropanol (16 mL) was quicklyadded 5 M HCl in isopropanyl (3.2 mL, 16 mmol). The mixture was warmedto 51° C. and stirred for 20 h. It was then concentrated to provide thetitle compound in 97 wt % purity (767 mg, 96%). MS (ESI): mass calcd.for C₇H₁₂N₂O₂, 156.1; m/z found, 157.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆): 9.9-9.2 (m, 2H), 4.73-4.71 (m, 1H), 4.42-4.37 (m, 1H), 4.1-3.9(m, 2H), 3.79-3.77 (m, 0.5H), 3.55-3.48 (m, 1H), 3.37-3.35 (m, 0.5H),3.25-3.07 (m, 2H), 2.00-1.82 (m, 2H).

Step C. A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (67 g, 0.26mol), 1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanonehydrochloride (40.61 g, 0.26 mol), Et₃N (183 mL, 1.31 mol), andN-methylpyrrolidinone (150 mL) in dichloroethane (750 mL) was stirred atrt for 1 h. Sodium triacetoxyborohydride (66.63 g, 0.314 mol) was thenadded in four equal portions over a 4 h period. After stirringovernight, the mixture was quenched with 3 N HCl_((aq)) (250 mL) andthen 6 N HCl_((aq)) (3×50 mL) to a final pH of 0.54. The layers wereseparated and the organic was extracted again with 3 N HCl_((aq)) (250mL). The combined aqueous layers were basified with Na₂CO₃ (50 g) andthen 50% NaOH_((aq)) (130 mL) to a final pH of 13.2. After stirring for1 h, isopropyl acetate (200 mL) was added and the mixture was stirredfor 20 min. After separation of layers, the aqueous was extracted withadditional isopropyl acetate (2×200 mL) and the organic layers werecombined with an interstitial oil and concentrated. The resulting brownoil was purified by flash chromatography (0-5% MeOH in CH₂Cl₂) toprovide the product as a clear oil (93.84 g, 91%).

The compounds in Examples 11-20 were prepared using methods analogous tothose described in Example 10, utilizing the appropriate carboxylic acidin the coupling reaction.

Example 11(S,S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(1-hydroxy-cyclopropyl)-methanone

MS (ESI): mass calcd. for C₂₃H₂₃N₃O₃S, 421.15; m/z found, 422.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=7.9 Hz, 1H),7.66 (d, J=8.0 Hz, 1H), 7.45-7.35 (m, 3H), 7.33-7.24 (m, 3H), 5.09 (brs, 0.5H), 4.72 (br s, 0.5H), 4.09-4.00 (m, 0.5H), 3.76 (s, 2H),3.71-3.57 (m, 1H), 3.55 (br s, 1H), 3.35 (d, J=10.8 Hz, 0.5H), 3.06-2.70(m, 2H), 2.01-1.86 (m, 1H), 1.77-1.65 (m, 1H), 1.27 (br m, 1H), 1.15 (brm, 1H), 1.09-0.81 (br m, 3H).

Example 12(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.3 Hz, 1H),7.67 (d, J=8.7 Hz, 1H), 7.43-7.36 (m, 3H), 7.33-7.24 (m, 3H), 4.86 (brm, 0.33H), 4.65 (br m, 0.67H), 4.22 (s, 1H), 3.84 (br m, 0.33H),3.79-3.71 (m, 3H), 3.57 (br m, 1H), 3.48 (br m, 0.33H), 3.37 (br m,0.67H), 3.02 (br m, 0.67H), 2.90 (br m, 0.33H), 2.73 (m, 0.33H), 2.60(br m, 0.67H), 2.00 (br m, 0.67H), 1.92 (m, 0.33H), 1.76 (br m, 0.67H),1.68 (br m, 0.33H), 1.52-1.42 (m, 5.67H).

Example 13(S,S,S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(tetrahydro-furan-3-yl)-methanone

MS (ESI): mass calcd. for C₂₄H₂₅N₃O₃S, 435.16; m/z found, 436.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.0 Hz, 1H),7.67 (d, J=7.7 Hz, 1H), 7.44-7.36 (m, 3H), 7.34-7.25 (m, 3H), 4.81 (brm, 0.5H), 4.34 (br m, 0.5H), 4.08 (br m, 1H), 3.93 (m, 1H), 3.86 (m,2H), 3.78 (s, 1H), 3.74 (m, 1.5H), 3.58 (br m, 1.5H), 3.39 (dd, J=8.5,2.2 Hz, 0.5H), 3.30 (dd, J=11.5, 2.2 Hz, 0.5H), 3.13 (m, 0.5H), 3.03 (m,0.5H), 2.86 (dd, J=9.3, 2.2 Hz, 0.5H), 2.74 (d, J=9.9 Hz, 0.5H), 2.57(d, J=9.3 Hz, 0.5H), 2.29 (m, 0.5H), 2.21 (m, 0.5H), 2.06 (m, 1H), 2.01(d, J=9.9 Hz, 0.5H), 1.92 (d, J=9.9 Hz, 0.5H), 1.79 (d, J=9.4 Hz, 0.5H),1.92 (d, J=9.9 Hz, 0.5H), 1.67 (d, J=9.9 Hz, 0.5H).

Example 14(S,S)-(2-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₆H₃₀N₄O₄S, 494.20; m/z found, 495.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.1 Hz, 1H),7.67 (d, J=7.9 Hz, 1H), 7.44-7.36 (m, 3H), 7.35-7.24 (m, 3H), 5.46 (brm, 1H), 4.79 (br m, 0.5H), 4.23 (br m, 0.5H), 3.99 (dd, J=12.9, 4.5 Hz,0.5H), 3.91-3.80 (m, 1.5H), 3.75 (m, 2.5H), 3.58 (br m, 1.5H), 3.30 (m,1H), 2.98 (br d, J=9.8 Hz, 0.5H), 2.87 (dd, J=9.9, 2.1 Hz, 0.5H), 2.72(br d, J=9.4 Hz, 0.5H), 2.58 (br d, J=9.7 Hz, 0.5H), 2.01 (br d, J=9.4Hz, 0.5H), 1.94 (br d, J=9.8 Hz, 0.5H), 1.78 (br d, J=9.8 Hz, 0.5H),1.67 (br d, J=9.8 Hz, 0.5H), 1.47 (s, 9H).

Example 15(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₃S, 409.14; m/z found, 410.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.3 Hz, 1H),7.66 (d, J=8.8 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 7.31-7.23 (m, 5H), 4.81(br s, 1H), 4.21 (br d, J=14.8 Hz, 0.5H), 4.09-3.96 (br m, 2H), 3.74 (brd, J=11.2 Hz, 0.5H), 3.64 (br s, 1H), 3.43 (br d, J=9.4 Hz, 0.5H), 3.33(br d, J=11.1 Hz, 0.5H), 3.20 (dd, J=9.3, 2.2 Hz, 0.5H), 3.08 (dd,J=9.4, 2.3 Hz, 0.5H), 2.97 (dd, J=9.7, 2.2 Hz, 1H), 2.89-2.75 (br m,4H), 2.73 (br d, J=9.8 Hz, 0.5H), 2.54 (br d, J=10.1 Hz, 0.5H), 1.98 (brd, J=9.8 Hz, 0.5H), 1.93 (br d, J=9.8 Hz, 0.5H), 1.77 (br d, J=9.9 Hz,0.5H), 1.68 (br d, J=10.6 Hz, 0.5H).

Example 16(S,S)-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1-cyclopropyl)-methanone

MS (ESI): mass calcd. for C₂₄H₂₅N₃O₃S, 435.16; m/z found, 436.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.72 (d, J=8.1 Hz, 1H),7.65 (d, J=8.1 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 7.30-7.23 (m, 5H), 5.08(br s, 0.5H), 4.71 (br s, 1.5H), 4.02 (br m, 0.5H), 3.67 (br m, 0.5H),3.56 (br m, 1.5H), 3.33 (br m, 0.5H), 2.97 (br m, 1H), 2.86-2.67 (br m,5H), 1.94-1.81 (br m, 1H), 1.76-1.63 (br m, 1H), 1.26 (br s, 1H),1.15-0.84 (br m, 3H).

Example 17(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₃S, 437.17; m/z found, 438.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.1 Hz, 1H),7.66 (d, J=8.3 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 7.30-7.23 (m, 5H), 4.83(br s, 0.5H), 4.66 (br s, 0.5H), 4.19 (br s, 1H), 3.81 (br d, J=9.5 Hz,0.5H), 3.66 (br d, J=11.6 Hz, 0.5H), 3.61-3.56 (br m, 1H), 3.46 (br d,J=9.2 Hz, 0.5H), 3.35 (br d, J=11.6 Hz, 0.5H), 3.09 (br d, J=8.7 Hz,0.5H), 2.99 (br d, J=9.3 Hz, 0.5H), 2.91-2.74 (br m, 4H), 2.67 (br d,J=9.4 Hz, 0.5H), 2.59 (br d, J=10.0 Hz, 0.5H), 1.98-1.83 (br m, 1H),1.77-1.64 (br m, 1H), 1.47 (s, 6H).

Example 18(S,S)-(5-{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1-hydroxy-cyclopropyl)-methanone

MS (ESI): mass calcd. for C₂₄H₂₅N₃O₃S, 435.16; m/z found, 436.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=7.7 Hz, 1H),7.67 (d, J=6.9 Hz, 1H), 7.41-7.32 (m, 2H), 7.29-7.26 (m, 1H), 7.22-7.18(br m, 2H), 7.13 (br d, J=7.2 Hz, 1H), 5.00 (br s, 0.5H), 4.69 (br s,0.5H), 3.97 (br s, 0.5H), 3.65-3.54 (br m, 2H), 3.33 (br s, 0.5H),3.09-2.91 (br m, 1H), 2.89-2.76 (br m, 4H), 2.69 (d, J=9.2 Hz, 1H), 1.88(br s, 1H), 1.69 (br s, 2H), 1.36-1.28 (br m, 1H), 1.14-0.87 (br m, 3H).

Example 19(S,S)-1-(5-{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₃S, 437.17; m/z found, 438.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.4 Hz, 1H),7.67 (d, J=8.9 Hz, 1H), 7.41-7.33 (m, 2H), 7.28 (m, 1H), 7.23-7.18 (m,2H), 7.13 (br d, J=7.0 Hz, 1H), 4.82 (br s, 0.5H), 4.61 (br s, 0.5H),4.12 (br s, 1H), 3.78 (br d, J=9.4 Hz, 0.5H), 3.65 (br d, J=11.7 Hz,0.5H), 3.57 (s, 1H), 3.44 (br d, J=9.3 Hz, 0.5H), 3.34 (br d, J=11.4 Hz,0.5H), 3.08 (br d, J=9.1 Hz, 0.5H), 2.97 (br d, J=9.8 Hz, 0.5H),2.90-2.74 (br m, 4H), 2.65 (br d, J=9.9 Hz, 0.5H), 2.57 (br d, J=9.3 Hz,0.5H), 1.93 (br d, J=9.8 Hz, 0.5H), 1.86 (br d, J=9.3 Hz, 0.5H),1.75-1.69 (m, 1H), 1.49-1.34 (m, 6H).

Example 20(S,S)-1-(5-{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₃S, 409.14; m/z found, 410.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=7.8 Hz, 1H),7.67 (d, J=9.1 Hz, 1H), 7.41-7.34 (m, 2H), 7.28 (m, 1H), 7.23-7.18 (m,2H), 7.13 (d, J=7.7 Hz, 1H), 4.78 (br s, 0.5H), 4.19 (br d, J=14.8 Hz,0.5H), 4.05-3.94 (br m, 2H), 3.71 (br d, J=11.6 Hz, 0.5H), 3.60 (br s,1H), 3.39 (dd, J=9.3, 1.1 Hz, 0.5H), 3.31 (dd, J=11.1, 2.4 Hz, 0.5H),3.17 (dd, J=9.3, 2.2 Hz, 0.5H), 3.05 (dd, J=9.7, 2.2 Hz, 0.5H), 2.94(dd, J=10.1, 2.2 Hz, 0.5H), 2.89-2.73 (br m, 4H), 2.70 (br d, J=9.8 Hz,0.5H), 2.51 (dd, J=9.4, 1.2 Hz, 0.5H), 1.95 (br d, J=9.2 Hz, 0.5H), 1.90(br d, J=9.9 Hz, 0.5H), 1.74 (br d, J=9.4 Hz, 0.5H), 1.65 (br d, J=9.8Hz, 0.5H), 1.26 (s, 1H).

The compounds in Examples 21-28 were prepared using methods analogous tothose described for Example 10, using the appropriate carboxylic acid,by replacing Et₃N with (iPr)₂NEt and by adding 1-hydroxybenzotriazole(HOBt) as a coupling reagent.

Example 21(R,R)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-methoxy-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₃S, 409.15; m/z found, 410.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H),7.68 (d, J=8.1 Hz, 1H), 7.45-7.35 (m, 3H), 7.35-7.28 (m, 2.5H),7.28-7.24 (m, 0.5H), 4.83 (s, 0.5H), 4.46 (s, 0.5H), 4.10-4.04 (m, 1H),4.03-3.99 (m, 1H), 3.76 (d, J=10.5 Hz, 2.5H), 3.65-3.53 (m, 1.5H), 3.44(dd, J=11.9, 3.7 Hz, 3H), 3.36-3.31 (m, 1H), 3.01 (dd, J=9.7, 2.2 Hz,0.5H), 2.87 (dd, J=9.8, 2.2 Hz, 0.5H), 2.78 (d, J=9.7 Hz, 0.5H), 2.57(dd, J=9.8, 0.9 Hz, 0.5H), 2.00 (d, J=8.0 Hz, 0.5H), 1.94 (d, J=8.0 Hz,0.5H), 1.77 (d, J=8.0 Hz, 0.5H), 1.67 (d, J=8.0 Hz, 0.5H).

Example 22(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methoxy-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₄S, 439.16; m/z found, 440.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=7.8 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 7.40 (d, J=1.2 Hz, 0.25H), 7.38 (s, 0.5H), 7.36(d, J=1.2 Hz, 0.25H), 7.30-7.22 (m, 3H), 6.98-6.91 (m, 2H), 4.81 (s,0.5H), 4.45 (s, 0.5H), 4.12-4.02 (m, 3H), 3.99 (s, 1H), 3.76-3.61 (m,2H), 3.44 (d, J=2.9 Hz, 3H), 3.38-3.33 (m, 1H), 3.19 (dd, J=9.7, 2.2 Hz,0.5H), 3.06-2.92 (m, 2.5H), 2.80 (d, J=9.8 Hz, 0.5H), 2.65 (dd, J=9.7,1.1 Hz, 0.5H), 1.97 (d, J=9.6 Hz, 0.5H), 1.92 (d, J=10.4 Hz, 0.5H), 1.76(d, J=9.7 Hz, 0.5H), 1.69 (d, J=10.0 Hz, 0.5H).

Example 23(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₄S, 425.14; m/z found, 426.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=7.7 Hz, 1H),7.66 (d, J=7.9 Hz, 1H), 7.41 (d, J=1.2 Hz, 0.25H), 7.39 (s, 0.5H), 7.37(d, J=1.2 Hz, 0.25H), 7.30-7.25 (m, 3H), 6.98-6.92 (m, 2H), 4.81 (s,0.5H), 4.23 (d, J=14.0 Hz, 0.5H), 4.12-3.97 (m, 4H), 3.82-3.70 (m,1.5H), 3.55 (s, 0.5H), 3.51-3.43 (m, 1H), 3.38 (dd, J=11.4, 1.9 Hz,0.5H), 3.24 (dd, J=9.4, 2.2 Hz, 0.5H), 3.19 (dd, J=9.8, 2.1 Hz, 0.5H),3.09-2.92 (m, 2.5H), 2.82 (d, J=9.8 Hz, 0.5H), 2.64 (dd, J=9.8, 1.2 Hz,0.5H), 2.00 (d, J=10.0 Hz, 0.5H), 1.94 (d, J=10.0 Hz, 0.5H), 1.79 (d,J=9.8 Hz, 0.5H), 1.71 (d, J=10.0 Hz, 0.5H).

Example 24(R,R)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.76-7.74 (m, 1H), 7.69(dd, J=8.0, 0.7 Hz, 1H), 7.46-7.39 (m, 3H), 7.36-7.29 (m, 3H), 4.89 (s,0.5H), 4.66 (s, 0.5H), 4.22 (s, 1H), 3.89-3.72 (m, 3H), 3.60 (s, 1H),3.52-3.38 (m, 0.5H), 3.07-3.03 (m, 0.5H), 2.95-2.91 (m, 0.5H), 2.77-2.73(m, 0.5H), 2.62 (d, J=9.4 Hz, 0.5H), 2.03 (d, J=10.2 Hz, 0.5H),1.97-1.92 (m, 0.5H), 1.79 (d, J=10.1 Hz, 0.5H), 1.73-1.65 (m, 1H),1.54-1.45 (m, 6H).

Example 25(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₄S, 453.17; m/z found, 454.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=8.1 Hz, 1H),7.66 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.3 Hz, 0.25H), 7.39-7.38 (m, 0.5H),7.36 (d, J=1.3 Hz, 0.25H), 7.30-7.23 (m, 3H), 6.98-6.92 (m, 2H), 4.85(s, 0.5H), 4.64 (s, 0.5H), 4.19 (s, 1H), 4.12-4.03 (m, 2H), 3.88 (d,J=9.9 Hz, 0.5H), 3.75-3.65 (m, 1.5H), 3.50 (d, J=8.9 Hz, 0.5H), 3.40(dd, J=11.8, 1.9 Hz, 0.5H), 3.21 (dd, J=9.8, 2.0 Hz, 0.5H), 3.09 (d,J=8.6 Hz, 0.5H), 3.05-2.95 (m, 2H), 2.74 (d, J=10.0 Hz, 0.5H), 2.68 (d,J=10.0 Hz, 0.5H), 2.03-1.89 (m, 1H), 1.82-1.66 (m, 1H), 1.48-1.44 (m,6H).

Example 26(R,R)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(1-hydroxy-cyclopropyl)-methanone

MS (ESI): mass calcd. for C₂₃H₂₃N₃O₃S, 421.15; m/z found, 422.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.75 (d, J=8.1 Hz, 1H),7.69 (d, J=8.0 Hz, 1H), 7.46-7.38 (m, 3H), 7.35-7.27 (m, 3H), 5.08 (brs, 0.5H), 4.75 (br s, 0.5H), 4.13-3.99 (m, 0.5H), 3.80 (br s, 2H),3.71-3.63 (m, 1H), 3.57 (br s, 1H), 3.42-3.34 (m, 0.5H), 3.06-2.97 (m,0.5H), 2.95-2.87 (m, 0.5H), 2.78-2.73 (m, 1H), 2.03-1.89 (m, 1H),1.81-1.67 (m, 1H), 1.42-1.29 (m, 1H), 1.23-1.09 (m, 1H), 1.08-1.01 (m,2H), 1.00-0.90 (m, 1H).

Example 27(S,S)-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1-hydroxy-cyclopropyl)-methanone

MS (ESI): mass calcd. for C₂₄H₂₅N₃O₄S, 451.16; m/z found, 452.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=7.6 Hz, 1H),7.65 (d, J=7.9 Hz, 1H), 7.40 (d, J=1.3 Hz, 0.25H), 7.38 (s, 0.5H), (d,J=1.3 Hz, 0.25H), 7.29-7.24 (m, 3H), 6.97-6.93 (m, 2H), 5.06 (s, 0.5H),4.71 (s, 0.5H), 4.11-4.03 (m, 3H), 3.67-3.60 (m, 2H), 3.37 (d, J=11.1Hz, 0.5H), 3.14 (d, J=8.7 Hz, 0.5H), 3.05-2.95 (m, 2H), 2.86-2.76 (m,1H), 1.96-1.89 (m, 1H), 1.73 (s, 2H), 1.30 (s, 1H), 1.17-0.87 (m, 3H).

Example 28(R,R)-(2-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₆H₃₀N₄O₄S, 494.20; m/z found, 495.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=7.7 Hz, 1H),7.68 (d, J=8.0 Hz, 1H), 7.43-7.36 (m, 3H), 7.33-7.25 (m, 3H), 5.50-5.41(m, 1H), 4.79 (s, 0.5H), 4.24 (s, 0.5H), 4.04-3.80 (m, 2H), 3.72-3.78(m, 2.5H), 3.62-3.54 (m, 1.5H), 3.34-3.26 (m, 1H), 2.99 (dd, J=9.8, 2.0Hz, 0.5H), 2.87 (dd, J=9.8, 2.1 Hz, 0.5H), 2.72 (d, J=9.7 Hz, 0.5H),2.59 (d, J=9.6 Hz, 0.5H), 2.01 (d, J=9.8 Hz, 0.5H), 1.95 (d, J=10.0 Hz,0.5H), 1.79 (d, J=9.5 Hz, 0.5H), 1.68 (d, J=9.8 Hz, 0.5H), 1.45 (s, 9H).

Example 29(R,R)-2-Amino-1-{5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

To a mixture of(R,R)-(2-{5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester (8.2 mg, 0.02 mmol) in CH₂Cl₂ (0.3 mL) was addedHCl (4.0 N in 1,4-dioxane, 0.3 mL). The solution was stirred for 2 h andconcentrated under a stream of dry nitrogen. Purification viapreparative reverse phase HPLC afforded the title compound (2.7 mg,38%). MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.15; m/z found, 395.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz,1H), 7.67 (d, J=7.9 Hz, 1H), 7.44-7.36 (m, 3H), 7.34-7.28 (m, 2H),7.28-7.23 (m, 1H), 4.81 (s, 0.5H), 4.21 (s, 0.5H), 3.81-3.72 (m, 2.5H),3.58 (s, 1H), 3.54-3.46 (m, 1H), 3.39-3.24 (m, 2.5H), 3.00 (dd, J=9.6,2.0 Hz, 0.5H), 2.86 (dd, J=9.7, 2.1 Hz, 0.5H), 2.76 (d, J=9.8 Hz, 0.5H),2.67-2.58 (m, 0.25H), 2.54 (d, J=9.6 Hz, 0.5H), 2.00 (d, J=9.6 Hz,0.5H), 1.93 (d, J=9.9 Hz, 0.5H), 1.86-1.30 (m, 2.75H).

Example 30(S,S)-[2-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester

This compound was prepared using methods analogous to those outlined inExample 28. MS (ESI): mass calcd. for C₂₇H₃₂N₄O₅S, 524.21; m/z found,525.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d,J=7.6 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.40 (d, J=1.3 Hz, 0.25H), 7.38(s, 0.5H), 7.36 (d, J=1.3 Hz, 0.25H), 7.30-7.23 (m, 3H), 6.97-6.91 (m,2H), 5.46 (d, J=16.9 Hz, 1H), 4.78 (s, 0.5H), 4.22 (s, 0.5H), 4.11-4.00(m, 2H), 3.98 (d, J=16.9 Hz, 0.25H), 3.90 (d, J=4.6 Hz, 0.25H),3.87-3.79 (m, 1.25H), 3.77-3.71 (m, 1H), 3.70 (s, 0.5H), 3.59 (d, J=9.5Hz, 0.5H), 3.49 (s, 0.25H), 3.36-3.28 (m, 1H), 3.17 (dd, J=9.7, 1.6 Hz,0.5H), 3.07-2.92 (m, 2.5H), 2.77 (d, J=9.7 Hz, 0.5H), 2.66 (dd, J=9.8,1.0 Hz, 0.5H), 2.03-1.97 (d, J=10.1 Hz, 0.5H), 1.93 (d, J=10.0 Hz,0.5H), 1.79 (d, J=10.0 Hz, 0.5H), 1.69 (d, J=10.0 Hz, 0.5H), 1.45 (s,9H).

Example 31(S,S)-2-Amino-1-(5-{2-[4-(benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

This compound was prepared using methods analogous to those outlined inExample 29. MS (ESI): mass calcd. for C₂₂H₂₄N₄O₃S, 424.16; m/z found,425.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73 (d,J=8.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.40 (d, J=1.2 Hz, 0.25H), 7.38(s, 0.5H), 7.36 (d, J=1.2 Hz, 0.25H), 7.30-7.23 (m, 3H), 6.97-6.92 (m,2H), 4.79 (s, 0.5H), 4.20 (s, 0.5H), 4.11-4.01 (m, 2H), 3.80-3.66 (m,1.5H), 3.56-3.47 (m, 1H), 3.40-3.24 (m, 2.5H), 3.19 (dd, J=9.6, 1.8 Hz,0.5H), 3.07-2.90 (m, 2.5H), 2.79 (d, J=9.7 Hz, 0.5H), 2.62 (d, J=9.5 Hz,0.5H), 1.99 (d, J=9.5 Hz, 0.5H), 1.91 (d, J=9.8 Hz, 0.5H), 1.84-1.43 (m,3H).

Example 32(S,S)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

To a stirred suspension of(S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride (2.8 g, 6.8 mmol) and Et₃N (9.1 mL, 68.5 mmol) in CH₂Cl₂(50 mL) was added trimethylsilylisocyanate (3.8 mL, 27.4 mmol), and theresulting solution was stirred at rt for 1.5 h. The solution was thenpartitioned between CH₂Cl₂ (500 mL) and satd. aq. NaHCO₃ (80 mL). Theorganic layer was separated, dried (Na₂SO₄), filtered and concentrated.Purification by silica gel flash chromatography (5% to 10% CH₃OH inCH₂Cl₂) afforded the title compound as a white solid (2.2 g, 85%).

Alternative Preparation:

Step A: 4-(Benzothiazol-2-yloxy)-benzaldehyde bisulfite complex. To asolution of 2-chlorobenzothiazole (33.7 g, 199 mmol) in CH₃CN (500 mL)was added 4-hydroxy benzaldehyde (24.3 g, 199 mmol) and K₂CO₃ (28 g, 199mmol). The heterogeneous mixture was heated at reflux for 72 h and thencooled to rt. The solids were removed by filtration and washed withCH₃CN (100 mL). To the filtrate was added an aqueous solution of NaHSO₃(26 g, 199 mmol, 66 mL water). After stirring for 3.5 h, the mixture wasfiltered and the wet cake was dried under vacuum overnight to afford thebisulfite complex (66 g, 92%) as a white powder. ¹H NMR (500 MHz,DMSO-d₆): 7.93 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.60-7.55 (m,2H), 7.44-7.39 (m, 1H), 7.35-7.29 (m, 3H), 6.03 (d, J=5.2 Hz, 1H), 5.04(d, J=5.2 Hz, 1H).

Step B: 4-(Benzothiazol-2-yloxy)-benzaldehyde. To a solution of thebisulfite complex (66 g, 184 mmol) in CH₂Cl₂ (600 mL) was added anaqueous solution of NaOH (9.2 g in 644 mL water, 230 mmol). Theresulting mixture was vigorously stirred at rt for 2 h. The product wasextracted with CH₂Cl₂ (200 mL), washed with satd. aq. NaCl (200 mL) anddried (MgSO₄). After filtration and evaporation of the solvent, thedesired aldehyde was obtained as a white solid (38 g, 81%). MS (ESI):mass calcd. for C₁₄H₉NO₂S, 255.04; m/z found, 256.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 10.05 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.8 (dd, J=8.7, 8.6Hz, 2H), 7.6 (d, J=8.6 Hz, 2H), 7.4 (td, J=8.6, 1.2 Hz, 1H), 7.3 (td,J=8.6, 1.2 Hz, 1H).

Step C: (S,S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid amidehydrochloride. To a solution of(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(35.6 g, 179 mmol) in CH₂Cl₂ (600 mL) was added trimethylsilylisocyanate(82.5 g, 716 mmol). After 2 h at rt, the mixture was concentrated, andthe resulting white solid was dissolved in CH₂Cl₂ (500 mL). The solutionwas then treated with a solution of HCl (4.0 N in 1,4-dioxane, 135 mL).The resulting heterogeneous suspension was then stirred at rt overnight.Upon evaporation of the solvents, the desired product was isolated as awhite solid (33 g), which was used directly in the next step. [Note: themass balance was found to be 104%, which arose from additional HCl thatcould not be removed by standard evaporation under vacuum]. ¹H NMR (500MHz, CD₃OD): 4.77 (s, 1H), 4.55 (s, 1H), 3.69 (d, J=12.1 Hz, 1H), 3.64(d, J=12.1 Hz, 1H), 3.47 (d, J=11.3 Hz, 1H), 3.40 (d, J=11.3 Hz, 1H),2.22 (d, J=11.5 Hz, 1H), 2.15 (d, J=11.5 Hz, 1H).

Step D:(S,S)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide. To a solution of(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid amidehydrochloride (35.6 g, 200 mmol) in THF (250 mL) was added Et₃N (62 mL,440 mmol), and the resulting suspension was stirred at rt for 5 min. Asolution of 4-(benzothiazol-2-yloxy)-benzaldehyde (38 g, 149 mmol) inTHF (320 mL) was added. The reaction mixture was allowed to stir at rtfor 2 h. Sodium triacetoxyborohydride (37.9 g, 180 mmol) was added in 3equal portions over 10 min at 0° C. The mixture was then stirred at rtovernight. The reaction was diluted with CH₂Cl₂ (500 mL) and 1 N NaOH(300 mL). The layers were allowed to separate and the aqueous layer wasfurther extracted with CH₂Cl₂ (300 mL). The combined organic layers werewashed with satd. aq. NaCl (200 mL), dried (MgSO₄) and concentrated. Thecrude material was dissolved in refluxing EtOAc (400 mL) for 5 h. Uponcooling the solution to rt, the product precipitated as a white solid.This solid was purified by silica gel flash chromatography (4:1CH₂Cl₂/CH₃OH) to afford the desired product (25 g, 44%) as a whitepowdery solid. The EtOAc solution recovered after filtration of thewhite solid was concentrated and purified by silica gel flashchromatography (4:1 CH₂Cl₂/CH₃OH) followed by recrystallization toprovide additional desired product as a white solid (8 g, 14%). MS(ESI): mass calcd. for C₂₀H₂₀N₄O₂S, 380.47; m/z found, 381.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.75 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.0, 0.7 Hz,1H), 7.44 (d, J=8.6 Hz, 2H), 7.42-7.39 (m, 1H), 7.35-7.26 (m, 3H),4.49-4.32 (m, 3H), 3.79 (s, 2H), 3.62-3.53 (m, 2H), 3.25 (dd, J=8.8, 2.2Hz, 1H), 2.93 (d, J=9.7 Hz, 1H), 2.77 (d, J=9.7 Hz, 1H), 1.95 (d, J=9.7Hz, 1H), 1.77 (d, J=9.7 Hz, 1H).

The compounds in Examples 33-40 were prepared using methods analogous tothose described in Example 32.

Example 33(S,S)-5-[3-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₀H₂₀N₄O₂S, 380.13; m/z found, 381.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.73 (d, J=7.9 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H),7.42-7.36 (m, 3H), 7.29-7.22 (m, 3H), 4.57-4.32 (m, 3H), 3.78 (s, 2H),3.55 (br s, 1H), 3.51 (br s, 1H), 3.21 (dd, J=8.8, 2.2 Hz, 1H), 2.90 (d,J=8.9 Hz, 1H), 2.73 (br d, J=9.2 Hz, 1H), 1.91 (br d, J=10.0 Hz, 1H),1.73 (br d, J=9.5 Hz, 1H).

Example 34(R,R)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₀H₂₀N₄O₂S, 380.13; m/z found, 381.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H),7.45-7.36 (m, 3H), 7.33-7.25 (m, 3H), 4.50-4.25 (m, 3H), 3.77 (s, 2H),3.52-3.50 (m, 2H), 3.24 (dd, J=8.8, 2.1 Hz, 1H), 2.91 (dd, J=9.5, 1.5Hz, 1H), 2.76 (d, J=9.5 Hz, 1H), 1.94 (d, J=9.5 Hz, 1H), 1.76 (d, J=9.4Hz, 1H).

Example 35(S,S)-5-(4-Benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄OS, 378.50; m/z found, 379.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 8.00 (d, J=7.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H),7.48-7.45 (m, 1H), 7.37-7.33 (m, 5H), 4.43-438 (br m, 5H), 3.74 (br s,2H), 3.53 (br s, 2H), 3.21 (dd, J=9.2, 2.0 Hz, 1H), 2.90 (dd, J=9.2, 2.0Hz, 1H), 2.74 (d, J=9.2 Hz, 1H), 1.92 (br d, J=9.2 Hz, 1H), 1.73 (br d,J=9.2 Hz, 1H).

Example 36meso-endo-[8-(4-Benzothiazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-urea

MS (ESI): mass calcd. for C₂₃H₂₆N₄OS, 406.55; m/z found, 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.99 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H),7.45 (dt, J=7.8, 1.2 Hz, 1H), 7.37-7.31 (m, 5H), 5.28 (br s, 1H), 4.59(br s, 2H), 4.42 (s, 2H), 3.84-3.82 (m, 1H), 3.57-3.55 (br m, 2H), 3.20(br s, 2H), 2.26-2.21 (br m, 2H), 2.10-2.05 (m, 2H), 1.89-1.87 (m, 2H),1.64 (br d, J=14.0 Hz, 2H).

Example 37meso-endo-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-urea

MS (ESI): mass calcd. for C₂₃H₂₆N₄O₂, 390.49; m/z found, 391.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.70-7.67 (m, 1H), 7.48-7.46 (m, 1H), 7.37-7.28(m, 6H), 5.06 (br s, 1H), 4.44 (br s, 2H), 4.26 (s, 2H), 3.83 (dd,J=6.4, 5.8 Hz, 1H), 3.51 (s, 2H), 3.18 (br s, 2H), 2.24-2.18 (m, 2H),2.11-2.08 (m, 2H), 1.82 (br d, J=8.4 Hz, 2H), 1.62 (br d, J=14.4 Hz,2H).

Example 38(S,S)-5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.15; m/z found, 395.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.77 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H),7.45-7.40 (m, 1H), 7.40-7.36 (m, 2H), 7.33-7.27 (m, 3H), 4.38 (br s,1H), 3.67 (br s, 1H), 3.60-3.48 (m, 1H), 3.27-3.22 (m, 1H), 3.00-2.94(m, 1H), 2.90-2.79 (br m, 4H), 2.70 (br d, J=9.9 Hz, 1H), 1.91 (br d,J=10.3 Hz, 1H), 1.79 (br d, J=9.3 Hz, 1H).

Example 39(S,S)-5{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl}2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.14; m/z found, 395.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.73 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H),7.42-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.23-7.18 (br m, 2H), 7.14 (br d,J=7.5 Hz, 1H), 4.41 (br s, 3H), 3.57 (br s, 1H), 3.46 (m, 1H), 3.18 (dd,J=8.8, 2.1 Hz, 1H), 2.98 (dd, J=9.5, 2.3 Hz, 1H), 2.90-2.74 (br m, 4H),2.69 (br d, J=9.6 Hz, 1H), 1.87 (br d, J=9.8 Hz, 1H), 1.72 (br d, J=9.6Hz, 1H).

Example 40(S,S)-5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₃S, 410.14; m/z found, 411.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.73 (d, J=7.7 Hz, 1H), 7.66 (dd, J=7.9, 0.7Hz, 1H), 7.40 (d, J=1.2 Hz, 0.25H), 7.38 (s, 0.5H), 7.36 (d, J=1.3 Hz,0.25H), 7.29-7.23 (m, 3H), 6.97-6.92 (m, 2H), 4.39 (s, 3H), 4.12-4.02(m, 2H), 3.69 (s, 1H), 3.54 (d, J=8.0 Hz, 1H), 3.25 (dd, J=8.9, 2.1 Hz,1H), 3.11-2.94 (m, 3H), 2.80 (d, J=9.6 Hz, 1H), 1.92 (d, J=9.6 Hz, 1H),1.82-1.68 (m, 1H).

Example 41(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-methoxy-ethanone

To a stirred solution of(S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride (144 mg, 0.35 mmol) and Et₃N (200 μL, 1.4 mmol) in CH₂Cl₂(15 mL) at rt was added methoxyacetyl chloride (50 μL, 0.53 mmol). After18 h at rt, the reaction mixture was partitioned between CH₂Cl₂ (150 mL)and satd. aq. NaHCO₃ (50 mL). The organic layer was separated, dried(Na₂SO₄), filtered and concentrated. Purification by silica gel flashchromatography (0% to 5% CH₃OH in CH₂Cl₂) afforded the title compound asa viscous, colorless oil (127 mg, 89%). MS (ESI): mass calcd. forC₂₂H₂₃N₃O₃S, 409.15; m/z found, 410.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃,mixture of rotamers): 7.74 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H),7.40 (m, 3H), 7.30 (m, 3H), 4.83 (br m, 0.5H), 4.46 (br m, 0.5H), 4.06(m, 1H), 4.01 (s, 1H), 3.76 (m, 2.5H), 3.63 (br d, J=9.3 Hz, 0.5H), 3.58(br s, 1H), 3.45 (s, 1.5H), 3.43 (s, 1.5H), 3.35 (br d, J=2.1 Hz, 0.5H),3.33 (m, 0.5H), 3.01 (dd, J=9.9, 2.3 Hz, 0.5H), 2.87 (dd, J=9.8, 2.2 Hz,0.5H), 2.78 (br d, J=9.9 Hz, 0.5H), 2.58 (d, J=9.5 Hz, 0.5H), 1.99 (brd, J=9.3 Hz, 0.5H), 1.96 (br d, J=9.8 Hz, 0.5H), 1.76 (br d, J=10.0 Hz,0.5H), 1.66 (br d, J=10.0 Hz, 0.5H).

The compounds in Examples 42-43 were prepared using methods analogous tothose described in Example 41.

Example 42(S,S)-1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methoxy-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.73 (d, J=7.8 Hz, 1H),7.66 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.29-7.23 (m, 5H), 4.79(br m, 0.5H), 4.43 (br m, 0.5H), 4.14-4.01 (br m, 1H), 3.97 (br s, 1H),3.68 (br m, 0.5H), 3.58 (br m, 1.5H), 3.43 (br s, 3H), 3.31 (d, J=11.5Hz, 1H), 3.07 (d, J=9.2 Hz, 0.5H), 2.95 (d, J=8.7 Hz, 0.5H), 2.88-2.68(m, 4H), 2.55 (d, J=9.6 Hz, 0.5H), 1.93 (d, J=9.1 Hz, 0.5H), 1.33-1.21(br m, 1H), 0.92-0.78 (br m, 1H).

Example 43(S,S)-1-(5-{2-[3-(Benzothiazol-2-yloxy)-phenyl]-ethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-methoxy-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=7.6 Hz, 1H),7.67 (d, J=8.7 Hz, 1H), 7.41-7.33 (m, 2H), 7.30-7.24 (m, 1H), 7.23-7.18(br m, 2H), 7.13 (br d, J=8.7 Hz, 1H), 4.78 (br s, 0.5H), 4.42 (br s,0.5H), 4.04 (dd, J=13.8, 6.0 Hz, 1H), 3.94 (dd, J=14.0, 1.0 Hz, 1H),3.66 (d, J=11.5 Hz, 0.5H), 3.60-3.53 (br m, 1.5H), 3.41 (br s, 3H),3.33-3.27 (br m, 1H), 3.06 (dd, J=9.9, 2.2 Hz, 0.5H), 2.93 (dd, J=9.8,2.2 Hz, 0.5H), 2.88-2.74 (br m, 4H), 2.70 (br d, J=9.3 Hz, 0.5H), 2.54(br d, J=9.5 Hz, 0.5H), 1.91 (br d, J=9.4 Hz, 0.5H), 1.86 (br d, J=9.9Hz, 0.5H), 1.71 (br d, J=10.0 Hz, 0.5H), 1.64 (br d, J=9.9 Hz, 0.5H).

Example 44(R,R)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone

Step A. Acetic acid(R,R)-2-{5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethylester. This compound was prepared using the methods outlined in Example41, substituting acetoxyacetyl chloride for methoxyacetyl chloride. MS(ESI): mass calcd. for C₂₃H₂₃N₃O₄S, 437.14; m/z found, 438.1 [M+H]⁺.

Step B.(R,R)-1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone.To acetic acid(R,R)-2-{5-[4-(benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-oxo-ethylester (161 mg, 0.37 mmol) in methanol (2 mL) was added macroporouspolystyrene-supported carbonate (592 mg, 3.11 mmol/g). The mixture wasplaced on an orbital shaker at 60° C. for 14 h. Filtration of themixture and purification via preparative reverse phase HPLC afforded theproduct (91 mg, 62%). MS (ESI): mass calcd. for C₂₁H₂₁N₃O₃S, 395.13; m/zfound, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.73(d, J=8.1 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.47-7.35 (m, 3H), 7.35-7.23(m, 3H), 4.82 (s, 0.5H), 4.20 (d, J=14.9 Hz, 0.5H), 4.13-3.96 (m, 2H),3.86-3.68 (m, 2.5H), 3.67-3.30 (m, 3H), 3.20 (dd, J=9.2, 2.2 Hz, 0.5H),2.98 (dd, J=9.7, 2.1 Hz, 0.5H), 2.87 (dd, J=9.8, 2.1 Hz, 0.5H), 2.76 (d,J=9.8 Hz, 0.5H), 2.56 (d, J=9.7 Hz, 0.5H), 2.07-1.84 (m, 1H), 1.77 (d,J=9.3 Hz, 0.5H), 1.67 (d, J=9.2 Hz, 0.5H).

Example 45(S,S)-2-[4-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzyl]-benzothiazole

To a solution of1-[5-(4-benzothiazol-2-ylmethyl-benzyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone(0.2 g, 0.49 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (0.41 mL, 3.0 mmol)and methanesulfonyl chloride (57 μL, 0.74 mmol) and the resultingsolution was stirred at rt for 14 h. The reaction mixture wasconcentrated and the crude residue was partitioned between EtOAc (50 mL)and brine (50 mL). The organic layer was separated, dried (Mg₂SO₄),filtered and concentrated. Purification by silica gel flashchromatography (0% to 15% CH₃OH in CH₂Cl₂) afforded the title compoundas clear oil (0.13 g, 62%). MS (ESI): mass calcd. for C₂₁H₂₃N₃O₂S₂,413.56; m/z found, 414.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.01 (d, J=7.8Hz, 1H), 7.81 (dd, J=7.8, 0.5 Hz, 1H), 7.49-7.45 (m, 1H), 7.37-7.34 (m,5H), 4.44 (d, J=2.0 Hz, 2H), 4.31 (br s, 1H), 3.80 (d, J=13.8 Hz, 1H),3.75 (d, J=13.8 Hz, 1H), 3.62-3.60 (m, 1H), 3.57 (br s, 1H), 3.24 (dd,J=9.3, 2.3 Hz, 1H), 2.90-2.89 (br m, 4H), 2.85-2.83 (br m, 1H),1.96-1.94 (m, 1H), 1.74-1.72 (m, 1H).

The compounds in Examples 46-49 were prepared using methods analogous tothose described in Example 45.

Example 46(R,R)-2-[4-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₁N₃O₃S₂, 415.10; m/z found, 416.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.76-7.71 (m, 1H), 7.69-7.66 (m, 1H), 7.45-7.36(m, 3H), 7.34-7.25 (m, 3H), 4.32 (br s, 1H), 3.86-3.73 (m, 2H),3.65-3.58 (m, 2H), 3.25 (dd, J=9.3, 2.2 Hz, 1H), 2.94-2.81 (m, 5H), 1.97(d, J=9.9 Hz, 1H), 1.75 (d, J=10.0 Hz, 1H).

Example 47(S,S)-2-{4-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.11; m/z found, 430.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.73 (d, J=6.6 Hz, 1H), 7.66 (d, J=6.7 Hz, 1H),7.38 (m, 1H), 7.30-7.24 (m, 5H), 4.31 (br m, 1H), 3.61 (br m, 1H), 3.56(br d, J=9.3 Hz, 1H), 3.23 (dd, J=9.4, 2.2 Hz, 1H), 2.98 (dd, J=9.9, 2.2Hz, 1H), 2.95-2.86 (br m, 4H), 2.85-2.73 (br m, 4H), 1.92 (br d, J=9.9Hz, 1H), 1.74 (br d, J=9.6 Hz, 1H).

Example 48(S,S)-2-{3-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]phenoxy}benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.11; m/z found, 430.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.74 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H),7.41-7.33 (m, 2H), 7.29-7.26 (m, 1H), 7.23-7.19 (m, 2H), 7.14 (br d,J=7.6 Hz, 1H), 4.28 (br s, 1H), 3.58 (br s, 1H), 3.52 (br d, J=9.4 Hz,1H), 3.21 (dd, J=9.3, 2.2 Hz, 1H), 2.97-2.87 (br m, 2H), 2.85 (s, 3H),2.83-2.75 (br m, 4H), 1.89 (br d, J=9.9 Hz, 1H), 1.71 (br d, J=9.9 Hz,1H).

Example 49(S,S)-2-{4-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₄S₂, 445.11; m/z found, 446.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.73 (d, J=7.6 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H),7.40 (d, J=8.0 Hz, 0.25H), 7.38 (s, 0.5H), 7.36 (d, J=1.3 Hz, 0.25H),7.29-7.24 (m, 3H), 6.97-6.93 (m, 2H), 4.31 (s, 1H), 4.11-4.04 (m, 2H),3.72 (s, 1H), 3.63 (dd, J=9.4, 0.9 Hz, 1H), 3.26 (dd, J=9.5, 2.2 Hz,1H), 3.11-2.98 (m, 3H), 2.91-2.88 (m, 4H), 1.96 (d, J=10.0 Hz, 1H), 1.76(d, J=10.0 Hz, 1H).

Example 50(S,S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-aceticacid tert-butyl ester

To a stirred solution of(S,S)-2-[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride (257 mg, 0.63 mmol) and bromoacetic acid tert-butyl ester(110 μL, 0.75 mmol) in CH₃CN (4.0 mL) at rt was added Et₃N (270 μL, 1.9mmol). After 18 h at rt, the suspension was partitioned between CH₂Cl₂(200 mL) and satd. aq. NaHCO₃ (80 mL). The organic layer was separated,dried (Na₂SO₄), filtered and concentrated. Purification by silica gelflash chromatography (5% CH₃OH in CH₂Cl₂) afforded the title compound asa viscous, colorless oil (218 mg, 77%). MS (ESI): mass calcd. forC₂₅H₂₉N₃O₃S, 451.19; m/z found, 452.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.75 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H),7.39 (m, 1H), 7.34-7.25 (m, 3H), 3.75 (m, 2H), 3.43 (br s, 1H), 3.33 (m,3H), 2.88 (m, 2H), 2.82 (br d, J=10.0 Hz, 1H), 2.70 (dd, J=10.0, 2.2 Hz,1H), 1.78 (s, 2H), 1.48 (s, 9H).

The compounds in Examples 51-52 were prepared using methods analogous tothose described in Example 1.

Example 51meso-1-{3-[4-(Benzothiazol-2-yloxy)-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.51; m/z found, 394.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H),7.43-7.35 (m, 3H), 7.34-7.24 (m, 3H), 4.65 (d, J=6.6 Hz, 1H), 4.07-4.01(m, 1H), 3.51 (q, J=13.4 Hz, 1H), 2.72 (dd, J=10.7, 2.5 Hz, 1H), 2.4(dd, J=10.7, 1.4 Hz, 2H), 2.25 (dd, J=10.5, 1.5 Hz, 1H), 2.07 (s, 3H),2.05-1.76 (m, 5H).

Example 52meso-endo-N-{8-[4-(Benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 407.54; m/z found, 408.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=7.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.47(d, J=8.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.35-7.25 (m, 3H), 5.85-5.76 (m,1H), 4.20-4.10 (m, 1H), 3.57 (s, 2H), 3.26-3.20 (m, 2H), 2.31-2.12 (m,4H), 1.99 (s, 3H), 1.83-1.75 (m, 2H), 1.67-1.59 (m, 2H).

The compounds in Examples 53-54 were prepared using methods analogous tothose described in Example 10.

Example 53meso-1-{3-[4-(Benzothiazol-2-yloxy)-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}-2-hydroxy-2-methyl-propan-1-one

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₃S, 437.57; m/z found, 438.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.77-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.45-7.38(m, 3H), 7.36-7.24 (m, 3H), 4.85-4.67 (m, 1H), 4.55-4.36 (m, 2H),3.66-3.42 (m, 2H), 2.78 (dd, J=11.2, 3.0 Hz, 1H), 2.44-2.27 (m, 3H),2.11-1.80 (m, 4H), 1.71-1.37 (m, 5H).

Example 54meso-endo-N-{8-[4-(Benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-2-hydroxy-2-methyl-propionamide

MS (ESI): mass calcd. for C₂₅H₂₉N₃O₃S, 451.59; m/z found, 452.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=8.1 Hz, 1H), 7.72-7.67 (m, 1H), 7.48(d, J=8.3 Hz, 2H), 7.43-7.38 (m, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.31-7.28(m, 1H), 7.23-7.16 (m, 1H), 4.18-4.01 (m, 1H), 3.66-3.53 (m, 2H),3.33-3.17 (m, 2H), 2.35-2.06 (m, 5H), 1.92-1.77 (m, 2H), 1.71-1.52 (m,7H).

The compounds in Examples 55-56 were prepared using methods analogous tothose described in Example 10 and Example 29.

Example 55meso-2-Amino-1-{3-[4-(benzothiazol-2-yloxy)-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}ethanone

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.53; m/z found, 409.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H),7.44-7.37 (m, 3H), 7.36-7.28 (m, 3H), 4.69 (d, J=6.6 Hz, 1H), 4.06-4.02(m, 1H), 3.60-3.36 (m, 4H), 2.81-2.68 (m, 2H), 2.37 (d, J=10.5 Hz, 1H),2.24 (d, J=9.8 Hz, 1H), 2.10-1.76 (m, 4H).

Example 56meso-endo-2-Amino-N-{8-[4-(benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}acetamide

MS (ESI): mass calcd. for C₂₃H₂₆N₄O₂S, 422.55; m/z found, 423.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 8.02-7.93 (m, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.69(dd, J=8.0, 0.7 Hz, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.43-7.38 (m, 1H),7.36-7.31 (m, 2H), 7.31-7.26 (m, 1H), 4.22-4.15 (m, 1H), 3.59 (s, 2H),3.34 (s, 2H), 3.28-3.21 (m, 2H), 2.30-2.21 (m, 2H), 2.20-2.13 (m, 2H),1.94-1.83 (m, 2H), 1.64 (d, J=14.0 Hz, 2H).

The compounds in Examples 57-58 were prepared using methods analogous tothose described in Example 45.

Example 57meso-2-[4-(8-Methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-3-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.56; m/z found, 430.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H),7.43-7.35 (m, 3H), 7.34-7.24 (m, 3H), 4.17-4.13 (m, 2H), 3.54 (s, 2H),2.92 (s, 3H), 2.74 (dd, J=10.9, 2.9 Hz, 2H), 2.39 (d, J=10.2 Hz, 2H),2.03-1.89 (m, 4H).

Example 58meso-endo-N-{8-[4-(Benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₅N₃O₃S₂, 443.59; m/z found, 444.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H),7.49-7.38 (m, 3H), 7.37-7.28 (m, 3H), 4.48 (d, J=6.7 Hz, 1H), 3.80-3.71(m, 1H), 3.55 (s, 2H), 3.28-3.19 (m, 2H), 2.98 (s, 3H), 2.40-2.22 (m,2H), 2.22-2.10 (m, 2H), 1.93-1.82 (m, 2H), 1.74 (d, J=14.0 Hz, 2H).

The compounds in Examples 59-60 were prepared using methods analogous tothose described in Example 32.

Example 59meso-3-[4-(Benzothiazol-2-yloxy)-benzyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.50; m/z found, 395.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.77-7.74 (m, 1H), 7.71-7.68 (m, 1H), 7.45-7.37(m, 3H), 7.37-7.28 (m, 3H), 4.45 (s, 2H), 4.18-4.06 (m, 2H), 3.53 (s,2H), 2.68 (dd, J=10.7, 2.6 Hz, 2H), 2.43-2.39 (m, 2H), 2.03-1.87 (m,4H).

Example 60meso-endo-{8-[4-(Benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.53; m/z found, 409.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.79-7.73 (m, 1H), 7.71-7.66 (m, 1H), 7.46 (d,J=8.6 Hz, 2H), 7.43-7.38 (m, 1H), 7.34-7.27 (m, 3H), 4.84 (d, J=7.0 Hz,1H), 4.36-4.27 (m, 2H), 3.93-3.85 (m, 1H), 3.56 (s, 2H), 3.26-3.19 (m,2H), 2.30-2.20 (m, 2H), 2.19-2.10 (m, 2H), 1.89-1.79 (m, 2H), 1.66 (d,J=13.9 Hz, 2H).

The compounds in Examples 61-68 were prepared using methods analogous tothose described in the preceding examples.

Example 61(S,S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-thiophen-2-yl-methanone

MS (ESI): mass calcd. for C₂₄H₂₁N₃O₂S₂, 447.11; m/z found, 448.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.76 (d, J=8.1 Hz, 1H),7.69 (dd, J=8.0, 0.7 Hz, 1H), 7.60 (s, 0.5H), 7.54-7.26 (m, 7.5H),7.15-7.06 (m, 1H), 4.97 (s, 0.5H), 4.76 (s, 0.5H), 4.01-3.55 (m, 5H),3.17-3.07 (m, 0.5H), 2.96 (s, 1H), 2.86-2.76 (m, 0.5H), 2.01 (d, J=9.8Hz, 1H), 1.89-1.79 (m, 1H).

Example 62(S,S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-(1H-pyrrol-2-yl)-methanone

MS (ESI): mass calcd. for C₂₄H₂₂N₄O₂S, 430.15; m/z found, 431.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 9.67-9.43 (m, 1H), 7.76(d, J=8.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.48-7.38 (m, 3H), 7.36-7.27(m, 3H), 7.01-6.93 (m, 1H), 6.62 (s, 0.75H), 6.51 (s, 0.25H), 6.35-6.25(m, 1H), 5.00-4.85 (m, 1H), 4.01-3.76 (m, 3H), 3.72-3.52 (m, 2H),3.21-3.12 (m, 0.25H), 2.98 (d, J=9.5 Hz, 0.75H), 2.90-2.75 (m, 1H),2.09-1.96 (m, 1H), 1.91-1.75 (m, 1H).

Example 63(S,S)-(1-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl}-cyclopropyl)-carbamicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₈H₃₂N₄O₄S, 520.21; m/z found, 521.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.76 (d, J=8.1 Hz, 1H),7.69 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 3H), 7.35-7.27 (m, 3H), 5.10 (brs, 1H), 4.74 (br s, 1H), 4.06 (br s, 0.5H), 3.79 (s, 2H), 3.66 (br s,0.5H), 3.54 (s, 1.5H), 3.40 (br s, 0.5H), 3.10-2.53 (m, 2H), 2.05-1.85(m, 1H), 1.69 (br s, 2H), 1.52-1.36 (m, 10H), 1.08-0.94 (m, 2H).

Example 64(S,S)-3-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl}-azetidine-1-carboxylicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₈H₃₂N₄O₄S, 520.21; m/z found, 521.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.75 (d, J=8.1 Hz, 1H),7.69 (d, J=7.9 Hz, 1H), 7.46-7.38 (m, 3H), 7.36-7.29 (m, 3H), 4.82 (s,0.5H), 4.31-3.99 (m, 4H), 3.80-3.76 (m, 1.25H), 3.75 (s, 1.25H), 3.59(d, J=13.2 Hz, 1H), 3.47-3.29 (m, 2H), 3.22 (dd, J=9.0, 2.2 Hz, 0.5H),3.04-2.96 (m, 0.5H), 2.88 (dd, J=9.8, 1.7 Hz, 0.5H), 2.78 (d, J=9.8 Hz,0.5H), 2.51 (dd, J=9.7, 0.9 Hz, 0.5H), 2.01 (d, J=9.5 Hz, 0.5H), 1.94(d, J=10.0 Hz, 0.5H), 1.76 (d, J=10.0 Hz, 0.5H), 1.66 (d, J=10.0 Hz,0.5H), 1.51-1.44 (m, 9.5H).

Example 65(S,S)-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-(1H-pyrrol-2-yl)-methanone

MS (ESI): mass calcd. for C₂₅H₂₄N₄O₃S, 460.16; m/z found, 461.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 9.59-9.38 (m, 1H), 7.75(d, J=7.7 Hz, 1H), 7.67 (dd, J=8.0, 0.7 Hz, 1H), 7.41 (d, J=1.3 Hz,0.25H), 7.40-7.39 (m, 0.5H), 7.38 (d, J=1.3 Hz, 0.25H), 7.32-7.25 (m,3H), 7.00-6.94 (m, 3H), 6.63-6.50 (m, 1H), 6.30 (dd, J=6.4, 2.7 Hz, 1H),4.99-4.84 (m, 1H), 4.09 (s, 2H), 3.99 (d, J=9.1 Hz, 0.75H), 3.91-3.72(m, 1.25H), 3.68 (d, J=9.8 Hz, 0.75H), 3.63-3.55 (m, 0.25H), 3.39-3.30(m, 0.25H), 3.15 (d, J=9.7 Hz, 0.75H), 3.11-2.98 (m, 2H), 2.88 (d, J=9.6Hz, 1H), 2.08-1.93 (m, 1H), 1.93-1.76 (m, 1H).

Example 66(S,S)-[1-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-cyclopropyl]-carbamicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₉H₃₄N₄O₅S, 550.22; m/z found, 551.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.75 (d, J=8.1 Hz, 1H),7.67 (d, J=7.95 Hz, 1H), 7.41 (d, J=1.0 Hz, 0.25H), 7.41-7.39 (m, 0.5H),7.38 (d, J=1.0 Hz, 0.25H), 7.32-7.25 (m, 3H), 6.99-6.94 (m, 2H),5.27-4.95 (m, 1H), 4.71 (br s, 1H), 4.12-4.03 (m, 2H), 3.67 (s, 1.25H),3.64-3.34 (m, 1.25H), 3.30-2.94 (m, 3H), 2.84-2.60 (m, 1H), 1.91 (br s,1H), 1.78-1.62 (m, 2H), 1.46 (s, 9H), 1.39-0.85 (m, 3.5H).

Example 67(S,S)-3-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-azetidine-1-carboxylicacid tert-butyl ester

MS (ESI): mass calcd. for C₂₉H₃₄N₄O₅S, 550.22; m/z found, 551.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=7.8 Hz, 1H),7.67 (d, J=7.9 Hz, 1H), 7.41 (d, J=1.1 Hz, 0.25H), 7.40 (s, 0.5H), 7.38(d, J=1.1 Hz, 0.25H), 7.32-7.25 (m, 3H), 6.99-6.93 (m, 2H), 4.80 (s,0.5H), 4.31-4.13 (m, 2H), 4.13-4.00 (m, 4H), 3.76-3.69 (m, 1.5H),3.50-3.28 (m, 2H), 3.24 (dd, J=9.2, 2.2 Hz, 0.5H), 3.19 (dd, J=9.7, 2.2Hz, 0.5H), 3.08-2.92 (m, 3H), 2.80 (d, J=9.6 Hz, 0.5H), 2.59 (dd, J=9.6,0.8 Hz, 0.5H), 1.98 (d, J=9.5 Hz, 0.5H), 1.93 (d, J=0.5 Hz, 0.5H), 1.77(d, J=9.5 Hz, 0.5H), 1.68 (d, J=10.0 Hz, 0.5H), 1.46 (d, J=1.5 Hz, 9H).

Example 68meso-endo-N-{8-[4-(4-Fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₃H₂₄FN₃O₂S, 425.5; m/z found, 426.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.50-7.42 (m, 3H), 7.36-7.32 (m, 2H), 7.26-7.21(m, 1H), 7.17-7.10 (m, 1H), 5.85-5.77 (m, 1H), 4.19-4.10 (m, 1H), 3.57(s, 2H), 3.23 (s, 2H), 2.30-2.11 (m, 4H), 1.99 (s, 3H), 1.83-1.75 (m,2H), 1.66-1.54 (m, 2H).

Example 69(S,S)-2-[3-(2,5-Diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride

This compound was prepared using the methods outlined in Example 1,Steps A and B, substituting the appropriate chloromethylphenoxy-benzothiazole. MS (ESI): mass calcd. for C₁₉H₁₉N₃OS, 337.12; m/zfound, 338.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): 7.86-7.78 (m, 2H),7.74-7.63 (m, 3H), 7.58 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 4.71 (br m,1H), 4.65 (br m, 1H), 4.56 (br m, 1H), 4.04 (br m, 1H), 3.86 (br d,J=13.2 Hz, 1H), 3.67 (m, 3H), 3.60 (br m, 1H), 2.77 (br m, 1H), 2.33 (brd, J=13.0 Hz, 1H).

Example 70meso-endo-N-{8-[4-(Benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-N-methyl-acetamide

To a stirring suspension of NaH (60% dispersion in mineral oil, 14 mg,0.34 mmol) in anhydrous DMF (600 μL) was added a solution ofmeso-endo-N-{8-[4-(benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide(100 mg, 0.24 mmol) in DMF (600 μL). After gas evolution ceased, methyliodide (16 μL, 0.26 mmol) was added via syringe. The reaction was warmedto 50° C. and allowed to stir overnight. The reaction was concentratedunder a stream of dry nitrogen and the resultant residue was dissolvedin CH₃OH (1.5 mL), filtered, and purified via reverse-phase HPLC toafford the title compound as white powder (10 mg, 10%). MS (ESI): masscalcd. for C₂₄H₂₇N₃O₂S, 421.6; m/z found, 422.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): 7.78 (d, J=8.1 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.6Hz, 2H), 7.45-7.38 (m, 1H), 7.37-7.25 (m, 3H), 3.95-3.80 (m, 1H), 3.61(s, 2H), 3.27-3.22 (m, 4H), 3.22-3.13 (m, 2H), 2.25-2.04 (m, 4H),2.01-1.86 (m, 4H), 1.69-1.65 (m, 2H).

The compounds in Examples 71-80 were prepared using methods analogous tothose described in the preceding examples.

Example 71meso-endo-N-{8-[4-(4-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₂S, 441.98; m/z found, 442.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.57-7.51 (m, 1H), 7.49-7.39 (m, 3H),7.37-7.30 (m, 2H), 7.24-7.16 (m, 1H), 5.85-5.79 (m, 1H), 4.17-4.08 (m,1H), 3.55 (s, 2H), 3.25-3.16 (m, 2H), 2.28-2.09 (m, 4H), 1.97 (s, 3H),1.84-1.73 (m, 2H), 1.65-1.57 (m, 2H).

Example 72meso-endo-N-{8-[4-(4-Methyl-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.57; m/z found, 422.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.52-7.39 (m, 3H), 7.35-7.30 (m, 2H), 7.25-7.13(m, 2H), 5.86-5.78 (m, 1H), 4.19-4.06 (m, 1H), 3.55 (s, 2H), 3.27-3.17(m, 2H), 2.61 (s, 3H), 2.31-2.10 (m, 3H), 1.97 (s, 2H), 1.81-1.73 (m,2H), 1.61-1.57 (m, 4H).

Example 73meso-endo-N-{8-[4-(6-Methyl-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.57; m/z found, 422.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.64-7.59 (m, 1H), 7.49-7.39 (m, 3H), 7.34-7.24(m, 2H), 7.23-7.15 (m, 1H), 5.87-5.72 (m, 1H), 4.16-4.08 (m, 1H),3.58-3.50 (m, 2H), 3.24-3.18 (m, 2H), 2.48-2.40 (m, 3H), 2.28-2.08 (m,4H), 1.97 (s, 3H), 1.80-1.69 (m, 2H), 1.60-1.54 (m, 2H).

Example 74meso-endo-1-(3-{[4-(Benzothiazol-2-yloxy)-benzyl]-methyl-amino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.57; m/z found, 422.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.75-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.43-7.18(m, 5H), 4.72-4.64 (m, 1H), 4.14-4.07 (m, 1H), 3.60-3.50 (m, 2H),2.60-2.48 (m, 1H), 2.26-1.75 (m, 15H).

Example 75meso-endo-3-{[4-(Benzothiazol-2-yloxy)-benzyl]-methyl-amino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₆N₄O₂S, 422.55; m/z found, 423.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.77-7.71 (m, 1H), 7.69-7.64 (m, 1H), 7.42-7.22(m, 5H), 4.56-4.49 (m, 1H), 4.22-4.07 (m, 1H), 3.58-3.53 (m, 2H),2.63-2.54 (m, 1H), 2.28-1.72 (m, 12H).

Example 76meso-8-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid amide

Step A: 4-(Benzothiazol-2-yloxy)-2-fluoro-benzoic acid. A solution of2-fluoro-4-hydroxy-benzoic acid (4.0 g, 25.6 mmol) in DMF (250 mL) wasadded Cs₂CO₃ (9.2 g, 28.2 mmol) and the reaction mixture was stirred at80° C. for 1 h prior to the addition of 2-chloro-benzothiazole (3.3 mL,25.6 mmol). The reaction mixture was stirred at 100° C. for 50 h, thencooled to rt, and the solid was filtered. The filtrate was diluted withEtOAc (200 mL) and water (100 mL), neutralized with 1 M HCl and theorganic layer was separated. The aqueous layer was extracted with EtOAc(2×200 mL). The organic layers were combined, dried (Na₂SO₄), filtered,and concentrated to afford the title compound as a colorless solid (4.7g, 63%). MS (ESI): mass calcd. for C₁₄H₈FNO₃S, 289.0; m/z found, 290.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.21 (t, J=8.5 Hz, 1H), 7.99 (d, J=8.5Hz, 1H), 7.87 (d, J=8.11 Hz, 1H), 7.63-7.45 (m, 4H).

Step B: [4-(Benzothiazol-2-yloxy)-2-fluoro-phenyl]-methanol. To asolution of 4-(benzothiazol-2-yloxy)-2-fluoro-benzoic acid (4.7 g, 16.1mmol) in THF (100 mL) was added Et₃N (2.5 mL, 17.7 mmol). The mixturewas cooled to 0° C., and isobutylchloroformate (2.1 mL, 16.1 mmol) wasadded. The reaction mixture was stirred for 2 h, filtered, andconcentrated. The residue was dissolved in THF (50 mL) and cooled to 0°C. Sodium borohydride (1.2 g, 32.2 mmol) was added and immediatelyfollowed by water (10 mL). The reaction mixture was then partitionedbetween EtOAc (50 mL) and brine (20 mL). The organic layer wasseparated, dried (Mg₂SO₄), filtered and concentrated. Purification bysilica gel flash chromatography (0% to 60% EtOAc in hexanes) affordedthe title compound as a colorless solid (3.3 g, 75%). MS (ESI): masscalcd. for C₁₄H₁₀FNO₂S, 275.0; m/z found, 276.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.77 (d, J=8.1 Hz, 1H), 7.72 (dd, J=5.3, 2.7 Hz, 1H), 7.54 (t,J=8.4 Hz, 1H), 7.43 (td, J=7.6, 1.3 Hz, 1H), 7.32 (td, J=7.5, 1.2 Hz,1H), 7.24-7.16 (m, 2H), 4.81 (d, J=5.8 Hz, 2H), 1.79 (t, J=6.1 Hz, 1H).

Step C: 2-(4-Chloromethyl-3-fluoro-phenoxy)-benzothiazole. This compoundwas prepared using methods analogous to those described for Example 4,Step B. MS (ESI): mass calcd. for C₁₄H₉ClFNOS, 293.0; m/z found, 294.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.75 (d, J=7.6 Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.49 (t, J=8.2 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.30 (t, J=7.3Hz, 1H), 7.24-7.18 (m, 2H), 4.65 (s, 2H).

Step D: 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid amidehydrochloride. A solution of 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (2.5 g, 11.7 mmol) in CH₂Cl₂ (50 mL) was treatedwith trimethylsilyl isocyanate (14 mL, 117 mmol). The resultant mixturewas stirred at rt for 4 h., concentrated and redissolved in CH₂Cl₂ (50mL). To this solution was added HCl (4.0 N in 1,4-dioxane, 12 mL), andthe resultant mixture was stirred at rt for 3 h. Concentration affordedthe title compound as a white powder (2.4 g, 99%). MS (ESI): mass calcd.for C₇H₁₃N₃O, 155.1; m/z found, 156.2 [M+H]⁺.

Step E:meso-8-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid amide. This compound was prepared using methods analogous to thosedescribed for Example 1, Step A, substituting3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide hydrochloride and2-(4-chloromethyl-3-fluoro-phenoxy)-benzothiazole for2-(4-chloromethyl-phenoxy)-benzothiazole and(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butylester. MS (ESI): mass calcd. for C₂₁H₂₁N₄O₂S, 412.1; m/z found, 413.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.75 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.63 (t, J=8.3 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.30 (t, J=7.2Hz, 1H), 7.22-7.09 (m, 2H), 4.51 (s, 2H), 3.58 (s, 2H), 3.56-3.46 (m,1H), 3.23 (s, 2H), 3.17 (d, J=11.3 Hz, 2H), 2.08-2.00 (m, 2H), 1.83 (s,1H), 1.74 (d, J=7.8 Hz, 2H).

Example 77meso-1-{8-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-3-yl}-ethanone

Step A: 1-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-ethanone hydrochloride.This compound was prepared using methods analogous to Example 76, StepD, substituting trimethylsilyl isocyanate with acetic anhydride. MS(ESI): MS (ESI): mass calcd. for C₈H₁₄N₂O, 154.1; m/z found, 155.1[M+H]⁺.

Step B:meso-1-{8-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-3,8-diaza-bicyclo[3.2.1]oct-3-yl}-ethanone.This compound was prepared using methods analogous to those describedfor Example 76, Step E. MS (ESI): mass calcd. for C₂₃H₂₄N₃O₂S, 425.1;m/z found, 426.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.8 Hz,1H), 7.69 (d, J=7.4 Hz, 1H), 7.64 (t, J=8.4, 1H), 7.4 (t, J=7.9 Hz, 1H),7.29 (t, J=6.9 Hz, 1H), 7.14 (m, 2H), 5.96-5.71 (m, 1H), 4.11 (m, 1H),3.56 (s, 2H), 3.23 (5, 2H), 2.21 (m, 4H), 1.97 (s, 3H), 1.86-1.71 (m,2H), 1.63 (d, J=14.3 Hz, 2H).

Example 78(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-2-hydroxy-ethanone

This compound was prepared using methods analogous to those describedfor Example 76, Step E, substituting(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterfor 3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide followed bymethods analogous to those described for Example 10. MS (ESI): masscalcd. for C₂₁H₂₀FN₃O₃S, 413.1; m/z found, 414.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.50 (td, J=8.5, 2.2 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.30 (t,J=7.7 Hz, 1H), 7.20-7.12 (m, 2H), 4.83 (s, 0.5H), 4.22 (d, J=14.9 Hz,0.5H), 4.08 (d, J=15.1 Hz, 1H), 4.01 (d, J=15.4 Hz, 1H), 3.86-3.69 (m,2.5H), 3.61 (s, 1H), 3.50-3.44 (m, 1.5H), 3.38 (dd, J=11.3, 1.7 Hz,0.5H), 3.23 (dd, J=9.3, 2.2 Hz, 0.5H), 3.00 (dd, J=9.7, 2.0 Hz, 0.5H),2.91 (dd, J=9.8, 2.1 Hz, 0.5H), 2.81 (d, J=9.8 Hz, 0.5H), 2.64 (d, J=9.7Hz, 0.5H), 2.04-1.94 (m, 1.5H), 1.78 (d, J=9.8 Hz, 0.5H), 1.69 (d,J=10.1 Hz, 0.5H).

Example 79(S,S)-1-{5-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

This compound was prepared using methods analogous to those describedfor Example 76, Step E, substituting(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterfor 3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide followed bymethods analogous to those described for Example 1, Steps B and C. MS(ESI): mass calcd. for C₂₁H₂₀FN₃O₂S, 397.1; m/z found, 398.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H), 7.69(d, J=8.1 Hz, 1H), 7.58-7.47 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.33-7.24(m, 1H), 7.22-7.07 (m, 2H), 4.79 (s, 0.5H), 4.25 (s, 0.5H), 3.86-3.67(m, 2.5H), 3.65-3.52 (m, 1.5H), 3.37-3.27 (m, 1H), 3.02 (dd, J=9.6, 2.1Hz, 0.5H), 2.89 (dd, J=9.7, 2.2 Hz, 1H), 2.81 (d, J=9.8 Hz, 1H), 2.65(d, J=9.6 Hz, 0.5H), 2.09 (s, 1.0H), 2.01 (s, 1.5H), 1.92 (d, J=10.0 Hz,0.5H), 1.81 (d, J=9.8 Hz, 0.5H), 1.69 (d, J=10.0 Hz, 0.5H).

Example 80(S,S)-5-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

This compound was prepared using methods analogous to those describedfor Example 76, Step E, substituting(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterfor 3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide followed bymethods analogous to those described for Example 32. MS (ESI): masscalcd. for C₂₀H₁₉FN₄O₂S, 398.1; m/z found, 399.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.74 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.52 (t,J=8.3 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.20-7.08(m, 2H), 4.66 (s, 2H), 4.44 (s, 1H), 3.79 (m, 2H), 3.63-3.49 (m, 2H),3.25 (d, J=7.0 Hz, 1H), 2.94 (d, J=8.0 Hz, 1H), 2.80 (d, J=9.5 Hz, 1H),1.93 (d, J=9.4 Hz, 1H), 1.76 (d, J=9.4 Hz, 1H).

The compounds in Examples 81-85 were prepared using methods analogous tothose described in Example 1, Steps A and B.

Example 812-[4-(Hexahydro-pyrrolo[3,4-b]pyrrol-5-ylmethyl)-phenoxy]-benzothiazolehydrochloride

MS (ESI): mass calcd. for C₂₀H₂₁N₃OS, 351.4; m/z found, 352.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.88-7.74 (m, 3H), 7.66 (d, J=8.1 Hz, 1H), 7.55(d, J=8.4 Hz, 2H), 7.45 (dt, J=8.2, 7.8, 1.3 Hz, 1H), 7.38-7.34 (m, 1H),4.75-4.42 (m, 3H), 4.13-3.99 (m, 1H), 3.83-3.48 (m, 7H), 2.35-2.00 (m,1H).

Example 822-[4-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-ylmethyl)-phenoxy]-benzothiazolehydrochloride

MS (ESI): mass calcd. for C₂₀H₂₁N₃OS, 351.4; m/z found, 352.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) 7.74 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H),7.42-7.34 (m, 3H), 7.33-7.21 (m, 3H), 3.87 (d, J=13.1 Hz, 1H), 3.70 (s,1H), 3.46 (d, J=13.1 Hz, 1H), 3.06-2.98 (m, 1H), 2.93-2.62 (m, 4H),2.50-2.44 (m, 1H), 2.19-2.01 (m, 2H), 1.46-1.29 (m, 1H).

Example 832-[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride

MS (ESI): mass calcd. for C₂₀H₂₁N₃O₂S, 351.5; m/z found, 352.2 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): 7.87-7.79 (m, 2H), 7.74 (d, J=8.2 Hz, 1H), 7.66(d, J=8.1 Hz, 1H), 7.57-7.50 (m, 2H), 7.48-7.42 (m, 1H), 7.39-7.32 (m,1H), 4.61-4.44 (m, 2H), 3.92-3.82 (m, 1H), 3.72-3.35 (m, 9H).

Example 842-[3-(Octahydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-phenoxy]-benzothiazolehydrochloride

MS (ESI): mass calcd. for C₂₁H₂₃N₃OS, 365.20; m/z found, 366.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 7.86-7.74 (m, 3H), 7.61 (d, J=7.6 Hz, 1H), 7.48(dd, J=8.6 Hz, 3.0, 2H), 7.44-7.37 (m, 1H), 7.34-7.26 (m, 1H), 4.64-4.48(m, 2H), 3.88-3.64 (m, 1H), 3.61-3.50 (m, 2H), 3.45-3.31 (m, 4H),3.26-3.07 (m, 2H), 3.04-2.64 (m, 2H), 2.23-1.81 (m, 2H).

Example 852-[4-(Octahydro-pyrrolo[3,4-c]pyridin-5-ylmethyl)-phenoxy]-benzothiazolehydrochloride

MS (ESI): mass calcd. for C₂₁H₂₃N₃OS, 365.16; m/z found, 366.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 11.66 (s, 1H), 9.81 (s, 1H), 9.55 (s, 1H),7.97 (d, J=7.3 Hz, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.1 Hz, 1H),7.55 (d, J=8.6 Hz, 2H), 7.45 (dt, J=7.8, 1.3 Hz, 1H), 7.35 (dt, J=7.5,1.2 Hz, 1H), 4.51-4.25 (m, 2H), 3.59-3.31 (m, 4H), 3.12-2.93 (m, 2H),2.87-2.62 (m, 2H), 2.39-2.16 (m, 1H), 2.14-2.01 (m, 1H), 1.99-1.72 (m,2H).

The compounds in Examples 86-90 were prepared using methods analogous tothose described in Example 1.

Example 861-{1-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.5; m/z found, 394.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.78-7.71 (m, 1H), 7.71-7.65 (m, 1H), 7.45-7.30(m, 6H), 3.98 (d, J=13.1 Hz, 0.5H), 3.88-3.77 (m, 1H), 3.75-3.62 (m,1H), 3.55 (d, J=13.3 Hz, 0.5H), 3.52-3.44 (m, 1H), 3.43-3.29 (m, 2H),3.22-3.15 (m, 0.5H), 3.15-3.08 (m, 1H), 3.07-3.01 (m, 0.5H), 2.92-2.76(m, 1H), 2.42-2.28 (m, 1H), 2.03 (s, 3H), 1.70-1.62 (m, 2H).

Example 871-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.5; m/z found, 394.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=8.1 Hz, 1H), 7.71-7.66 (m, 1H),7.46-7.35 (m, 3H), 7.36-7.28 (m, 3H), 4.49-4.44 (m, 1H), 4.34-4.27 (m,0.5H), 3.99-3.90 (m, 0.5H), 3.68 (d, J=13.1 Hz, 1H), 3.63-3.52 (m, 2H),3.48 (d, J=13.2 Hz, 1H), 3.45-3.35 (m, 0.5H), 3.07-2.93 (m, 0.5H),2.92-2.79 (m, 1H), 2.72-2.63 (m, 1H), 2.63-2.52 (m, 1H), 2.51-2.41 (m,1H), 2.08 (s, 3H), 1.95-1.83 (m, 1H).

Example 881-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.5; m/z found, 394.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H),7.43-7.35 (m, 3H), 7.34-7.23 (m, 3H), 3.76-3.59 (m, 4H), 3.47-3.41 (m,1H), 3.37-3.28 (m, 1H), 2.98-2.77 (m, 2H), 2.69-2.58 (m, 2H), 2.55-2.44(m, 2H), 2.06 (s, 3H).

Example 891-{2-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridin-5-yl}-ethanone

MS (ESI): mass calcd. C₂₃H₂₅N₃O₂S, 407.2; m/z found, 408.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H), 7.67(d, J=8.0 Hz, 1H), 7.43-7.20 (m, 6H), 3.89 (dd, J=13.4, 5.4 Hz, 0.5H),3.71-3.46 (m, 3.5H), 3.41-3.20 (m, 2H), 2.80-2.70 (m, 2H), 2.53-2.22 (m,4H), 2.07 (s, 3H), 1.94-1.61 (m, 2H).

Example 901-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridin-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₂S, 407.17; m/z found, 408.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H),7.67 (d, J=7.9 Hz, 1H), 7.42-7.35 (m, 3H), 7.35-7.24 (m, 3H), 3.68-3.37(m, 5.5H), 3.35-3.24 (m, 0.5H), 2.70-2.14 (m, 6H), 2.05 (s, 1.5H), 2.04(s, 1.5H), 1.83-1.67 (m, 1H), 1.67-1.51 (m, 1H).

Example 91cis-1-{7-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-[1,7]naphthyridin-1-yl}-ethanone

Step A:cis-6-[4-(Benzothiazol-2-yloxy)-benzyl]-decahydro-[1,6]naphthyridine.This compound was prepared using methods analogous to those describedfor Example 81. Separation from the trans-isomer was performed usingflash column chromatography. MS (ESI): mass calcd. C₂₂H₂₅N₃OS, 379.2;m/z found, 380.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.82 (d, J=8.0 Hz,1H), 7.76 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.57-7.49 (m, 2H),7.46-7.38 (m, 1H), 7.38-7.29 (m, 1H), 4.50 (s, 2H), 3.92-2.99 (m, 7H),2.69-2.29 (m, 2H), 2.27-2.01 (m, 2H), 2.06-1.65 (m, 2H), 1.28 (s, 1H),1.00-0.75 (m, 1H).

Step B:cis-1-{7-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-[1,7]naphthyridin-1-yl}-ethanone.This compound was prepared using methods analogous to those describedfor Example 1, Step C. MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.18;m/z found, 422.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃, mixture of rotamers):7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.44-7.35 (m, 3H),7.34-7.23 (m, 3H), 4.77-4.60 (m, 0.6H), 4.56-4.47 (m, 0.4H), 3.81-3.69(m, 0.4H), 3.64-3.55 (m, 0.6 1H), 3.53-3.36 (m, 2H), 3.20-3.05 (m,0.6H), 3.03-2.84 (m, 1H), 2.80-2.55 (m, 1.4H), 2.32-1.98 (m, 7H),1.88-1.66 (m, 2H), 1.55-1.35 (m, 3H).

Example 92trans-1-{7-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-[1,7]naphthyridin-1-yl}-ethanone

Step A:trans-6-[4-(Benzothiazol-2-yloxy)-benzyl]-decahydro-[1,6]naphthyridine.This compound was prepared using methods analogous to those describedfor Example 81. Separation from the cis-isomer was performed using flashcolumn chromatography. MS (ESI): mass calcd. C₂₂H₂₅N₃OS, 379.2; m/zfound, 380.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.83 (d, J=7.9 Hz, 1H),7.74 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.1 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H),7.43 (dt, J=8.2, 7.8, 1.3 Hz, 1H), 7.37-7.31 (m, 1H), 4.42 (s, 2H),3.81-3.59 (m, 2H), 3.61-3.36 (m, 2H), 3.29-2.96 (m, 4H), 2.37-1.93 (m,4H), 1.94-1.72 (m, 2H), 1.53-1.27 (m, 1H).

Step B:trans-1-{7-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-[1,7]naphthyridin-1-yl}-ethanone.This compound was prepared using methods analogous to those describedfor Example 1, Step C. MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.18;m/z found, 422.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=8.1 Hz,1H), 7.67 (d, J=7.9 Hz, 1H), 7.44-7.35 (m, 3H), 7.34-7.24 (m, 3H),3.66-3.41 (m, 2H), 3.40-3.23 (m, 2H), 3.09-2.77 (m, 2H), 2.30-2.14 (m,2H), 2.08 (s, 3H), 2.02-1.87 (m, 1H), 1.87-1.52 (m, 6H), 1.22-1.04 (m,1H).

Example 93(R,S)-N-{3-[4-(Benzothiazol-2-yloxy)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-acetamide

Step A:3-[4-(Benzothiazol-2-yloxy)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine.This compound was prepared using methods analogous to those describedfor Example 81. MS (ESI): mass calcd. C₁₉H₁₉N₃OS, 338.1; m/z found,380.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.93 (d, J=7.2 Hz, 1H), 7.69(d, J=7.5 Hz, 1H), 7.54-7.25 (m, 6H), 3.56 (s, 2H), 3.35-3.04 (m, 3H),2.88 (d, J=8.7 Hz, 2H), 2.34 (d, J=8.4 Hz, 2H), 1.32-1.30 (m, 2H).

Step B:(R,S)-N-{3-[4-(Benzothiazol-2-yloxy)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-\/1}-acetamide.This compound was prepared using methods analogous to those describedfor Example 1, Step C. MS (ESI): mass calcd. C₂₁H₂₁N₃O₂S, 379.1; m/zfound, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.77 (d, J=7.8 Hz, 1H),7.65 (d, J=8.0 Hz, 1H), 7.46-7.37 (m, 3H), 7.36-7.25 (m, 3H), 3.62 (s,2H), 3.09 (d, J=8.9 Hz, 2H), 2.98 (s, 1H), 2.45 (d, J=8.6, 2H), 1.88 (s,3H), 1.53 (s, 2H).

Example 941-(5-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-ethanone

These compounds were prepared using methods analogous to those describedfor Example 9. MS (ESI): Mass calcd for C₂₃H₂₅N₃O₃S, 423.5; m/z found,424.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.75 (d, J=8.0 Hz, 1H), 7.65 (d,J=8.1 Hz, 1H), 7.44-7.39 (m, 1H), 7.35-7.21 (m, 3H), 7.09-6.96 (m, 2H),4.15 (t, J=5.5 Hz, 2H), 3.72 (dd, J=11.1, 8.5 Hz, 1H), 3.61 (dd, J=12.4,7.9 Hz, 1H), 3.48-3.38 (m, 2H), 3.03-2.91 (m, 1H), 2.91-2.81 (m, 5H),2.63-2.46 (m, 2H), 2.05 (s, 3H).

Example 952-Amino-1-{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl}-ethanone

To a stirred solution of2-[4-(hexahydro-pyrrolo[3,4-b]pyrrol-5-ylmethyl)-phenoxy]-benzothiazolehydrochloride (100 mg, 0.26 mmol) and Et₃N (215 μL, 1.6 mmol) in CH₂Cl₂(2 mL) was added N-Boc-glycine (95 mg, 0.5 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.5mmol). The resulting solution was then stirred at rt for 16 h. Theresulting mixture was then treated with trifluoroacetic acid (1 mL) atrt for 3 h. The crude solid was dissolved in CH₃OH/DMSO (2:1) andpurified via reverse phase preparative HPLC to yield the title compoundas a fluffy white solid (37 mg, 35%). MS (ESI): mass calcd. forC₂₂H₂₄N₄O₂S, 408.5; m/z found, 409.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.74 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.43-7.33 (m, 3H),7.33-7.26 (m, 3H), 4.51-4.42 (m, 1H), 4.27-4.19 (m, 0.5H), 4.02-3.92 (m,0.5H), 3.66 (d, J=13.2 Hz, 1H), 3.58 (d, J=5.0 Hz, 0.5H), 3.51-3.37 (m,3H), 3.28 (d, J=16.7 Hz, 0.5H), 2.91-2.76 (m, 2H), 2.70-2.60 (m, 1H),2.58-2.50 (m, 1H), 2.50-2.37 (m, 1H), 2.14-1.96 (m, 1H), 1.97-1.80 (m,1H).

The compounds in Examples 96-97 were prepared using methods analogous tothose described in Example 95.

Example 962-Amino-1-{1-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.5; m/z found, 409.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.71 (d, J=8.1 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H),7.40-7.33 (m, 3H), 7.32-7.22 (m, 3H), 4.07-3.93 (m, 0.5H), 3.93-3.70 (m,2.5H), 3.67-3.58 (m, 1H), 3.54-3.32 (m, 4H), 3.31-3.15 (m, 1H),3.13-3.01 (m, 1H), 2.96-2.84 (m, 0.5H), 2.81-2.71 (m, 0.5H), 2.46-2.27(m, 1H), 2.12-1.95 (m, 1H), 1.72-1.53 (m, 1H).

Example 972-Amino-1-{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.5; m/z found, 409.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.79-7.73 (m, 1H), 7.71-7.67 (m, 1H), 7.43-7.36(m, 3H), 7.35-7.27 (m, 3H), 3.83-3.73 (m, 1H), 3.67-3.57 (m, 3H),3.53-3.37 (m, 3H), 3.31-3.23 (m, 1H), 3.00-2.80 (m, 2H), 2.70-2.61 (m,2H), 2.59-2.48 (m, 2H).

Example 98N-(2-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl}-2-oxo-ethyl)-2,2,2-trifluoro-acetamide

To a stirred solution of2-[4-(hexahydro-pyrrolo[3,4-b]pyrrol-5-ylmethyl)-phenoxy]-benzothiazolehydrochloride (100 mg, 0.26 mmol) and Et₃N (215 μL, 1.6 mmol) in CH₂Cl₂(2 mL) was added N-Boc-glycine (95 mg, 0.5 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (104 mg, 0.5mmol). The resulting solution was then stirred at rt for 16 h. Theresulting mixture was then treated with trifluoroacetic acid (1 mL) atrt for 3 h. The crude solid was dissolved in CH₃OH/DMSO (2:1) andpurified via reverse phase preparative HPLC to yield the title compoundas a fluffy white solid (26 mg, 20%). MS (ESI): mass calcd. forC₂₄H₂₃F₃N₄O₃S, 504.5; m/z found, 505.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.74 (d, J=7.7 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.56-7.49 (m, 1H),7.42-7.26 (m, 6H), 4.55-4.45 (m, 1H), 4.17-3.87 (m, 2H), 3.67 (d, J=13.1Hz, 1H), 3.60-3.38 (m, 3H), 3.09-2.81 (m, 2H), 2.78-2.54 (m, 2H),2.52-2.35 (m, 1H), 2.20-2.06 (m, 1H), 2.02-1.87 (m, 1H).

Example 99Azetidin-3-yl-{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone

This compound was prepared using methods analogous to Example 95,substituting HCl (4.0 N in dioxane) for trifluoroacetic acid. MS (ESI):Mass calcd for C₂₄H₂₆N₄O₂S, 434.6; m/z found, 435.2 [M+H]⁺; ¹H NMR (400MHz, CD₃OD): 7.80-7.72 (m, 1H), 7.68-7.57 (m, 1H), 7.53-7.36 (m, 2H),7.36-7.21 (m, 2H), 7.15-7.03 (m, 2H), 6.77-6.64 (m, 1H), 4.39-4.23 (m,2H), 4.11-3.94 (m, 0.5H), 3.94-3.82 (m, 1.5H), 3.81-3.66 (m, 1.5H),3.66-3.38 (m, 4.5H), 3.00-2.73 (m, 2H), 2.73-2.55 (m, 2H), 2.53-2.42 (m,1H), 2.42-2.26 (m, 1H).

The compounds in Examples 100-103 were prepared using methods analogousto those described in Example 10.

Example 100(R)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(tetrahydro-furan-2-yl)-methanone

MS (ESI): mass calcd. for C₂₅H₂₇N₃O₃S, 449.6; m/z found, 450.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.67 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.38-7.26 (m, 3H), 7.25-7.16 (m, 3H), 4.53-4.43 (m, 1H), 3.90-3.80 (m,1H), 3.77-3.71 (m, 1H), 3.67 (dd, J=11.3, 8.4 Hz, 1H), 3.59-3.49 (m,3H), 3.49-3.38 (m, 2H), 3.38-3.29 (m, 1H), 2.89-2.79 (m, 1H), 2.79-2.68(m, 1H), 2.67-2.48 (m, 2H), 2.40-2.30 (m, 2H), 2.17-1.95 (m, 1H),1.96-1.68 (m, 3H).

Example 101(S)-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(tetrahydro-furan-2-yl)-methanone

MS (ESI): mass calcd. for C₂₅H₂₇N₃O₃S, 449.6; m/z found, 450.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.66 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H),7.39-7.26 (m, 3H), 7.25-7.15 (m, 3H), 4.52-4.43 (m, 1H), 3.90-3.78 (m,1H), 3.78-3.70 (m, 1H), 3.66 (dd, J=11.3, 8.4 Hz, 1H), 3.58-3.50 (m,3H), 3.49-3.40 (m, 1H), 2.90-2.77 (m, 1H), 2.78-2.68 (m, 1H), 2.66-2.47(m, 2H), 2.45-2.28 (m, 2H), 2.18-1.96 (m, 1H), 1.95-1.72 (m, 3H).

Example 102{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(tetrahydro-furan-3-yl)-methanone

MS (ESI): mass calcd. for C₂₆H₂₇N₃O₃S, 449.6; m/z found, 450.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.66 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.39-7.26 (m, 3H), 7.25-7.14 (m, 3H), 3.85 (td, J=11.8, 8.2 Hz, 1H),3.80-3.56 (m, 4H), 3.53 (s, 1H), 3.52-3.45 (m, 1H), 3.45-3.29 (m, 2H),3.20-3.13 (m, 1H), 2.93-2.68 (m, 2H), 2.65-2.48 (m, 2H), 2.45-2.32 (m,2H), 2.11-1.88 (m, 2H).

Example 103{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone

MS (ESI): Mass calcd for C₂₆H₂₉N₃O₃S, 463.6; m/z found, 464.2 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD): 7.78 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H),7.49 (d, J=8.5 Hz, 2H), 7.45-7.38 (m, 1H), 7.36 (d, J=8.6 Hz, 2H),7.34-7.26 (m, 1H), 3.85-3.70 (m, 3H), 3.64-3.51 (m, 2H), 3.09-2.95 (m,1H), 2.96-2.83 (m, 3H), 2.83-2.70 (m, 1H), 2.70-2.55 (m, 2H), 2.55-2.43(m, 1H), 1.87-1.53 (m, 8H).

The compounds in Examples 104-115 were prepared using methods analogousto those described in Example 41.

Example 104{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-cyclobutyl-methanone

MS (ESI): mass calcd. for C₂₅H₂₇N₃O₂S, 433.6; m/z found, 434.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.67 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.38-7.26 (m, 3H), 7.25-7.16 (m, 3H), 3.52 (s, 2H), 3.50-3.40 (m, 2H),3.35 (dd, J=12.4, 3.9 Hz, 1H), 3.26-3.22 (m, 1H), 2.86-2.65 (m, 2H),2.60 (ddd, J=9.9, 7.2, 3.1 Hz, 2H), 2.36-2.30 (m, 2H), 2.23-1.97 (m,4H), 1.96-1.79 (m, 1H), 1.77-1.67 (m, 1H).

Example 105{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-pyrazin-2-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₃N₅O₂S, 457.6; m/z found, 458.2 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 8.97 (d, J=1.4 Hz, 1H), 8.69 (d, J=2.6 Hz, 1H),8.66 (dd, J=2.5, 1.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.67 (d, J=7.7 Hz,1H), 7.48 (d, J=8.4 Hz, 2H), 7.45-7.41 (m, 1H), 7.37-7.28 (m, 3H),3.97-3.85 (m, 2H), 3.79-3.70 (m, 2H), 3.71-3.62 (m, 2H), 3.02-2.89 (m,2H), 2.76 (dd, J=9.3, 6.6 Hz, 1H), 2.67 (dd, J=9.3, 6.7 Hz, 1H), 2.62(dd, J=9.5, 2.8 Hz, 1H), 2.51 (dd, J=9.5, 2.8 Hz, 1H).

Example 106{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-furan-2-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₃N₃O₃S, 445.5; m/z found, 446.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD) 7.65 (d, J=8.0 Hz, 1H), 7.59 (d, J=1.0 Hz, 1H),7.53 (d, J=8.1 Hz, 1H), 7.37-7.24 (m, 3H), 7.22-7.14 (m, 3H), 6.99 (d,J=3.5 Hz, 1H), 6.47 (dd, J=3.5, 1.8 Hz, 1H), 4.03-3.82 (m, 1H),3.80-3.63 (m, 2H), 3.62-3.54 (m, 1H), 3.52 (s, 2H), 2.97-2.68 (m, 2H),2.66-2.33 (m, 4H).

Example 107{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-thiophen-2-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₃N₃O₂S₂, 461.6; m/z found, 462.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 7.97-7.88 (m, 1H), 7.76 (d, J=5.0 Hz, 1H),7.69 (d, J=7.5 Hz, 1H), 7.56 (dd, J=3.8, 1.0 Hz, 1H), 7.47-7.28 (m, 6H),7.14 (dd, J=5.0, 3.7 Hz, 1H), 4.09-3.68 (m, 2H), 3.69-3.42 (m, 4H),3.07-2.67 (m, 2H), 2.61-2.40 (m, 4H).

Example 108{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-(1-methyl-1H-pyrrol-3-yl)-methanone

MS (ESI): mass calcd. for C₂₆H₂₆N₄O₂S, 458.6; m/z found, 459.2 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 7.80-7.74 (m, 1H), 7.70-7.61 (m, 1H), 7.50-7.38(m, 3H), 7.37-7.26 (m, 3H), 6.84-6.76 (m, 1H), 6.54-6.45 (m, 1H),6.12-6.02 (m, 1H), 3.88-3.79 (m, 2H), 3.79 (s, 3H), 3.74-3.67 (m, 2H),3.65 (d, J=7.6 Hz, 2H), 2.95-2.85 (m, 2H), 2.75-2.68 (m, 2H), 2.54-2.42(m, 2H).

Example 109{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-thiophen-3-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₃N₃O₂S₂, 461.6; m/z found, 462.1 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 7.81 (dd, J=2.9, 1.3 Hz, 1H), 7.79 (dd, J=8.0,0.5 Hz, 1H), 7.67 (dd, J=8.1, 0.5 Hz, 1H), 7.51-7.45 (m, 3H), 7.45-7.40(m, 1H), 7.36-7.28 (m, 4H), 3.92-3.77 (m, 2H), 3.76-3.69 (m, 1H),3.69-3.61 (m, 2H), 3.61-3.50 (m, 1H), 2.99-2.84 (m, 2H), 2.80-2.62 (m,2H), 2.62-2.37 (m, 2H).

Example 110{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-furan-3-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₃N₃O₃S, 445.5; m/z found, 446.2 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 7.99 (d, J=0.8 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H),7.67 (d, J=8.2 Hz, 1H), 7.59-7.54 (m, 1H), 7.49-7.46 (m, 2H), 7.46-7.40(m, 1H), 7.36-7.30 (m, 3H), 6.77-6.75 (m, 1H), 4.00-3.73 (m, 2H),3.74-3.59 (m, 4H), 3.55-3.41 (m, 1H), 3.06-2.83 (m, 2H), 2.79-2.65 (m,2H), 2.63-2.46 (m, 2H).

Example 111{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-cyclopropyl-methanone

MS (ESI): mass calcd. for C₂₄H₂₅N₃O₂S, 419.6; m/z found, 420.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.65 (d, J=7.3 Hz, 1H), 7.54 (d, J=8.1 Hz, 1H),7.40-7.25 (m, 3H), 7.24-7.14 (m, 3H), 3.76 (dd, J=11.0, 8.6 Hz, 1H),3.60-3.41 (m, 4H), 3.33 (dd, J=12.5, 4.2 Hz, 1H), 2.92-2.79 (m, 1H),2.79-2.67 (m, 1H), 2.58-2.55 (m, 2H), 2.38 (ddd, J=19.2, 9.4, 4.1 Hz,2H), 1.72-1.62 (m, 1H), 0.83-0.63 (m, 4H).

Example 1121-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-2-fluoro-ethanone

MS (ESI): Mass calcd for C₂₂H₂₂N₃O₂SF, 411.5; m/z found, 412.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.76 (d, J=7.9 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H),7.46-7.37 (m, 3H), 7.34-7.25 (m, 3H), 5.08-4.99 (m, 1H), 4.97-4.87 (m,1H), 4.79 (s, 2H), 3.71-3.55 (m, 3H), 3.54-3.41 (m, 1H), 3.03-2.78 (m,2H), 2.72-2.62 (m, 2H), 2.55-2.46 (m, 2H).

Example 1131-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-3,3,3-trifluoro-propan-1-one

MS (ESI): Mass calcd for C₂₃H₂₂N₃O₂SF₃, 461.5; m/z found, 462.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.76 (d, J=8.0 Hz, 1H), 7.68-7.60 (m, 1H),7.48-7.35 (m, 3H), 7.35-7.23 (m, 3H), 3.80-3.66 (m, 2H), 3.64 (s, 2H),3.51-3.41 (m, 2H), 3.38 (dd, J=10.2, 2.2 Hz, 2H), 3.01-2.83 (m, 2H),2.74-2.62 (m, 2H), 2.59-2.45 (m, 2H).

Example 114{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-isoxazol-5-yl-methanone

MS (ESI): Mass calcd for C₂₄H₂₂N₄O₃S, 446.5; m/z found, 447.2 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD): 7.80 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H),7.56-7.47 (m, 2H), 7.46-7.40 (m, 1H), 7.39-7.34 (m, 2H), 7.34-7.26 (m,1H), 4.78 (s, 2H), 3.84-3.70 (m, 3H), 3.70-3.58 (m, 2H), 3.57-3.52 (m,1H), 3.06-2.80 (m, 4H), 2.61-2.36 (m, 2H).

Example 115{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-morpholin-4-yl-methanone

MS (ESI): mass calcd. for C₂₅H₂₈H₄O₃S, 464.6; m/z found, 465.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.72 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H),7.45-7.32 (m, 3H), 7.32-7.20 (m, 3H), 3.64-3.58 (m, 4H), 3.56 (s, 2H),3.46 (dd, J=11.3, 7.5 Hz, 2H), 3.33-3.26 (m, 2H), 3.26-3.19 (m, 4H),2.79-2.68 (m, 2H), 2.65 (dd, J=9.3, 7.0 Hz, 2H), 2.36 (dd, J=9.4, 3.5Hz, 2H).

The compounds in Examples 116-117 were prepared using methods analogousto those described in Example 21.

Example 1161-{2-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridin-5-yl}-2-hydroxy-ethanone

MS (ESI): mass calcd. C₂₃H₂₅N₃O₃S 423.2; m/z found, 424.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃, mixture of rotamers): 7.75 (d, J=8.1 Hz, 1H), 7.67 (d,J=7.9 Hz, 1H), 7.40-7.38 (m, 3H), 7.35-7.25 (m, 3H), 4.13-4.12 (m, 2H),3.91 (dd, J=13.4, 5.4 Hz, 0.5H), 3.77-3.59 (m, 3.5H), 3.48-3.33 (m,1.5H), 3.28 (dd, J=13.3, 5.3 Hz, 0.5H), 3.21-3.13 (m, 1H), 2.82-2.64 (m,2H), 2.54-2.30 (m, 4H), 1.94-1.82 (m, 1H), 1.76-1.66 (m, 1H).

Example 1171-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridin-2-yl}-2-hydroxy-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H),7.67 (d, J=7.7 Hz, 1H), 7.43-7.34 (m, 3H), 7.35-7.24 (m, 3H), 4.21-3.93(m, 2H), 3.82-3.27 (m, 6.5H), 3.20-3.06 (m, 0.5H), 2.71-2.12 (m, 6H),1.88-1.67 (m, 1H), 1.57 (m, J=3.9 Hz, 1H).

Example 1181-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-2-hydroxy-ethanone

This compound was prepared using methods analogous to those describedfor Example 44, substituting macroporous polystyrene-supported carbonatein methanol with lithium hydroxide in THF/water/CH₃OH/CH₂Cl₂. MS (ESI):mass calcd. for C₂₂H₂₃N₃O₃S, 409.51; m/z found, 410.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 7.49 (d, J=7.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),7.40-7.33 (m, 3H), 7.32-7.27 (m, 3H), 4.10 (s, 2H), 3.83-3.82 (m, 1H),3.63-3.62 (m, 2H), 3.56-3.51 (m, 2H), 3.20-3.17 (m, 1H), 2.64-2.60 (m,2H), 2.59-2.53 (m, 4H).

Example 1195-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonicacid amide

Step A: tert-Butoxycarbonyl-5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonicacid amide. To a stirred solution of tert-butanol (72 μL, 0.75 mmol) inCH₂Cl₂ (3 mL) cooled to 0° C. was added chlorosulfonyl isocyanate (65μL, 0.75 mmol) dropwise via syringe. The resulting solution was allowedto stir at 0° C. for 30 min before being added dropwise to a solution of2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazoledihydrochloride (317 mg, 0.75 mmol) and Et₃N (520 μL, 3.75 mmol) inCH₂Cl₂ (2 mL). The resultant solution was stirred at rt for 2 h. Thecrude reaction mixture was concentrated to dryness under a stream of dryN₂. The crude solid was dissolved in CH₃OH/DMSO (2:1) and purified viareverse phase preparative HPLC to yield the title compound as a fluffywhite solid (114 mg, 29%). MS (ESI): mass calcd. for C₂₅H₃₀N₄O₅S₂,530.7; m/z found, 531.2 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 7.69 (d, J=8.0Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.35-7.29 (m,1H), 7.27-7.17 (m, 3H), 3.65 (s, 2H), 3.39 (dd, J=10.3, 7.2 Hz, 2H),3.15 (dd, J=10.3, 2.9 Hz, 2H), 2.87-2.77 (m, 2H), 2.78-2.67 (m, 2H),2.42 (dd, J=9.3, 3.5 Hz, 2H), 1.38 (s, 9H).

Step B:5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonicacid amide. To a stirred solution tert-butoxycarbonyl-5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonicacid amide (108 mg, 0.20 mmol) in CH₂Cl₂ (5 mL) was addedtrifluoroacetic acid (1 mL). The homogeneous reaction mixture wasallowed to stir overnight at rt. The crude reaction mixture was blowndown to dryness and dissolved in CH₃OH/DMSO (2:1) and purified viareverse phase preparative HPLC to afford the title compound as fluffywhite powder (60 mg, 70%). MS (ESI): mass calcd. for C₂₀H₂₂N₄O₃S₂,430.6; m/z found, 431.1 [M+H]⁺; ¹H NMR (500 MHz, CD₃OD): 7.79 (d, J=8.0Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.52-7.46 (m, 2H), 7.46-7.39 (m, 1H),7.37-7.27 (m, 3H), 3.68 (s, 2H), 3.24 (dd, J=9.5, 7.0 Hz, 2H), 3.06 (dd,J=9.4, 2.6 Hz, 2H), 2.93-2.87 (m, 2H), 2.87-2.78 (m, 2H), 2.40 (dd,J=8.5, 3.6 Hz, 2H).

The compounds in Examples 120-130 were prepared using methods analogousto those described in Example 45.

Example 1202-{4-[5-(Pyridine-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd for C₂₅H₂₄N₄O₃S₂, 492.6; m/z found, 493.1 [M+H]⁺;¹H NMR (500 MHz, DMSO-d₆) 8.96 (dd, J=2.3, 0.6 Hz, 1H), 8.94 (dd, J=4.8,1.6 Hz, 1H), 8.21 (ddd, J=8.0, 2.3, 1.7 Hz, 1H), 7.94 (dd, J=8.0, 0.7Hz, 1H), 7.74 (ddd, J=8.0, 4.8, 0.7 Hz, 1H), 7.70 (dd, J=8.1, 0.6 Hz,1H), 7.46-7.41 (m, 1H), 7.38-7.31 (m, 3H), 7.25-7.21 (m, 2H), 3.51 (s,2H), 2.81 (dd, J=9.9, 4.3 Hz, 2H), 2.74-2.65 (m, 2H), 2.43 (dd, J=9.2,6.4 Hz, 2H), 2.30 (dd, J=9.3, 2.4 Hz, 2H).

Example 1212-{4-[5-(Furan-2-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₄H₂₃N₃O₄S₂, 481.6; m/z found, 482.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 8.13-8.08 (m, 1H), 7.98-7.90 (m, 1H), 7.70(d, J=8.1 Hz, 1H), 7.49-7.37 (m, 3H), 7.36-7.28 (m, 3H), 7.25 (d, J=2.7Hz, 1H), 6.81 (dd, J=3.5, 1.8 Hz, 1H), 3.55 (s, 2H), 3.48-3.36 (m, 2H),2.90 (dd, J=10.1, 4.6 Hz, 2H), 2.79-2.66 (m, 2H), 2.42 (dd, J=9.2, 6.2Hz, 2H), 2.35 (dd, J=9.2, 2.2 Hz, 2H).

Example 1222-{4-[5-(1-Methyl-1H-imidazole-4-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₄H₂₅N₅O₃S₂, 495.6; m/z found, 496.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 7.94 (d, J=8.0 Hz, 1H), 7.89-7.81 (m, 2H),7.70 (d, J=7.5 Hz, 1H), 7.46-7.30 (m, 6H), 3.73 (s, 3H), 3.59-3.51 (m,2H), 2.91 (dd, J=9.8, 4.2 Hz, 2H), 2.73-2.63 (m, 2H), 2.56-2.40 (m, 4H),2.37-2.28 (m, 3H).

Example 1232-{4-[5-(1-Methyl-1H-pyrrole-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₅H₂₆N₄O₃S₂, 494.9; m/z found 496.1 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 7.85-7.76 (m, 2H), 7.76-7.72 (m, 1H), 7.68 (d,J=8.2 Hz, 1H), 7.48-7.39 (m, 3H), 7.38-7.27 (m, 3H), 3.82 (s, 3H), 3.64(s, 2H), 3.10 (dd, J=9.9, 3.3 Hz, 2H), 2.82-2.70 (m, 4H), 2.38 (dd,J=9.1, 3.7 Hz, 2H).

Example 1242-{4-[5-(Thiophene-2-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₄H₂₃N₃O₃S₃, 497.6; m/z found, 498.1 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 7.91 (dd, J=5.0, 1.3 Hz, 1H), 7.80 (d, J=7.6Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.65 (dd, J=3.8, 1.3 Hz, 1H), 7.47-7.40(m, 1H), 7.40-7.35 (m, 2H), 7.35-7.30 (m, 3H), 7.29 (dd, J=5.0, 3.8 Hz,1H), 3.62 (s, 2H), 3.03 (dd, J=9.9, 3.8 Hz, 2H), 2.87-2.77 (m, 2H), 2.70(dd, J=9.6, 6.9 Hz, 2H), 2.38 (dd, J=9.3, 3.5 Hz, 2H).

Example 1252-{4-[5-(Thiophene-3-sulfonyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₄H₂₃N₃O₃S₃, 497.6; m/z found, 498.1 [M+H]⁺;¹H NMR (500 MHz, CD₃OD): 8.15 (dd, J=3.0, 1.3 Hz, 1H), 7.80 (d, J=7.6Hz, 1H), 7.71 (dd, J=5.1, 3.1 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.46-7.41(m, 1H), 7.41-7.35 (m, 3H), 7.35-7.30 (m, 3H), 3.62 (s, 2H), 3.26 (dd,J=9.8, 7.5 Hz, 2H), 3.00 (dd, J=9.8, 3.6 Hz, 2H), 2.83-2.74 (m, 2H),2.69 (dd, J=9.4, 6.8 Hz, 2H), 2.37 (dd, J=9.2, 3.5 Hz, 2H).

Example 1262-[4-(5-Cyclopropanesulfonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S₂, 455.6; m/z found, 456.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆): 7.93 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.6 Hz,1H), 7.48-7.36 (m, 5H), 7.36-7.29 (m, 1H), 3.61 (s, 1H), 3.46 (dd,J=9.9, 7.6 Hz, 2H), 3.02 (dd, J=10.0, 4.0 Hz, 2H), 2.91-2.75 (m, 2H),2.70-2.61 (m, 1H), 2.57 (dd, J=9.1, 6.6 Hz, 2H), 2.38 (dd, J=9.2, 2.9Hz, 2H), 1.02-0.88 (m, 4H).

Example 1272-[4-(1-Methanesulfonyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.5; m/z found, 430.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=8.1 Hz, 1H), 7.71-7.68 (m, 1H),7.44-7.37 (m, 3H), 7.35-7.26 (m, 3H), 4.23-4.16 (m, 1H), 3.69-3.63 (m,1H), 3.59-3.49 (m, 2H), 3.47-3.38 (m, 1H), 3.03-2.98 (m, 1H), 2.95-2.88(m, 1H), 2.84 (s, 3H), 2.63-2.53 (m, 2H), 2.49-2.43 (m, 1H), 2.11-2.02(m, 1H), 1.92-1.84 (m, 1H).

Example 1282-[4-(5-Methanesulfonyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.5; m/z found, 430.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.75 (d, J=8.0 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H),7.44-7.24 (m, 6H), 3.90-3.82 (m, 1H), 3.51 (d, J=13.1 Hz, 1H), 3.48-3.42(m, 1H), 3.37-3.30 (m, 1H), 3.27-3.18 (m, 3H), 3.10-3.03 (m, 1H), 2.88(s, 3H), 2.41-2.32 (m, 1H), 2.13-2.05 (m, 1H), 1.76-1.57 (m, 2H).

Example 1292-[4-(5-Methanesulfonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₃S₂, 429.5; m/z found, 430.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.74 (d, J=7.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H),7.43-7.35 (m, 3H), 7.34-7.27 (m, 3H), 3.62 (s, 2H), 3.50-3.44 (m, 2H),3.16-3.07 (m, 2H), 2.96-2.81 (m, 5H), 2.71-2.60 (m, 2H), 2.51-2.41 (m,2H).

Example 1302-[4-(5-Methanesulfonyl-octahydro-pyrrolo[3,4-c]pyridin-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. C₂₂H₂₅N₃O₃S₂ 443.1; m/z found, 444.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.73 (d, J=8.1 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H),7.42-7.34 (m, 3H), 7.33-7.22 (m, 3H), 3.70 (s, 2H), 3.35-3.32 (m, 2H),3.25-3.07 (m, 2H), 2.82-2.68 (m, 5H), 2.67-2.50 (m, 2H), 2.49-2.42 (m,1H), 2.36-2.26 (m, 1H), 1.95-1.73 (m, 2H).

The compounds in Examples 131-143 were prepared using methods analogousto those described in Example 32.

Example 1315-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid (furan-2-ylmethyl)-amide

MS (ESI): mass calcd for C₂₆H₂₆N₄O₃S, 474.6; m/z found, 475.2 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD) 7.70-7.64 (m, 1H), 7.55 (d, J=8.1 Hz, 1H),7.39-7.29 (m, 3H), 7.28 (d, J=1.0 Hz, 1H), 7.25-7.17 (m, 3H), 6.21 (dd,J=3.2, 1.9 Hz, 1H), 6.10 (d, J=2.4 Hz, 1H), 4.22 (s, 2H), 3.54 (s, 2H),3.40 (dd, J=10.6, 8.0 Hz, 2H), 2.85-2.72 (m, 2H), 2.67 (dd, J=9.4, 7.1Hz, 2H), 2.33 (dd, J=9.5, 3.8 Hz, 2H).

Example 1325-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid pyridin-4-yl amide

MS (ESI): mass calcd. for C₂₆H₂₅N₅O₂S, 471.6; m/z found, 472.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 8.18 (dd, J=5.0, 1.6 Hz, 2H), 7.68 (dd, J=8.0,0.7 Hz, 1H), 7.55 (dd, J=8.1, 0.5 Hz, 1H), 7.47 (dd, J=5.0, 1.6 Hz, 2H),7.37 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 1H), 7.25-7.17 (m, 3H), 3.66-3.47(m, 4H), 3.40 (dd, J=11.0, 3.1 Hz, 2H), 2.93-2.77 (m, 2H), 2.65 (dd,J=9.5, 6.9 Hz, 2H), 2.44 (dd, J=9.5, 3.3 Hz, 2H).

Example 1335-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid (3,5-dimethyl-isoxazol-4-yl)-amide

MS (ESI): mass calcd. for C₂₆H₂₇N₅O₃S, 489.6; m/z found, 490.2 [M+H]⁺;¹H NMR (400 MHz, CD₃OD): 7.68 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H),7.40 (d, J=8.7 Hz, 2H), 7.36-7.28 (m, 1H), 7.28-7.17 (m, 3H), 3.59 (s,2H), 3.55 (dd, J=10.8, 8.2 Hz, 2H), 3.31 (dd, J=10.8, 3.2 Hz, 2H),2.92-2.78 (m, 2H), 2.68 (dd, J=9.5, 7.0 Hz, 2H), 2.44 (dd, J=9.6, 3.4Hz, 2H), 2.19 (s, 3H), 2.06 (s, 3H).

Example 1345-{2-[4-(Benzothiazol-2-yloxy)-phenoxy]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

MS (ESI): Mass calcd for C₂₂H₂₄N₄O₃S, 424.5; m/z found, 425.2 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD): 7.76 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H),7.44-7.39 (m, 1H), 7.35-7.32 (m, 3H), 7.08-7.03 (m, 2H), 4.20-4.06 (m,2H), 3.51 (dd, J=10.8, 7.8 Hz, 2H), 3.36-3.33 (m, 2H), 3.03-2.84 (m,6H), 2.49 (dd, J=9.1, 3.8 Hz, 2H).

Example 1355-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.5; m/z found, 395.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.76 (d, J=7.6 Hz, 1H), 7.71-7.67 (m, 1H),7.43-7.36 (m, 3H), 7.34-7.27 (m, 3H), 4.37 (s, 2H), 4.33-4.26 (m, 1H),3.68 (d, J=13.2 Hz, 1H), 3.56-3.44 (m, 3H), 2.96-2.84 (m, 2H), 2.69-2.62(m, 1H), 2.57-2.47 (m, 2H), 2.16-2.00 (m, 1H), 1.91-1.83 (m, 1H).

Example 1361-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.5; m/z found, 395.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.74 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H),7.43-7.38 (m, 3H), 7.35-7.24 (m, 3H), 4.33 (s, 2H), 3.89 (d, J=13.1 Hz,1H), 3.65-3.55 (m, 1H), 3.51-3.40 (m, 2H), 3.40-3.25 (m, 2H), 3.22-3.14(m, 1H), 3.13-3.05 (m, 1H), 2.94-2.80 (m, 1H), 2.42-2.33 (m, 1H),2.12-2.01 (m, 1H), 1.74-1.62 (m, 1H).

Example 137(S,S)-1-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.5; m/z found, 395.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.73 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H),7.42-7.35 (m, 3H), 7.35-7.23 (m, 3H), 4.33 (s, 2H), 3.91 (d, J=13.1 Hz,1H), 3.63-3.55 (m, 1H), 3.51-3.40 (m, 2H), 3.40-3.26 (m, 2H), 3.22-3.12(m, 1H), 3.13-3.06 (m, 1H), 2.94-2.80 (m, 1H), 2.42-2.33 (m, 1H),2.12-2.01 (m, 1H), 1.72-1.61 (m, 1H).

Example 138(R,R)-1-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.5; m/z found, 395.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.74 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H),7.43-7.38 (m, 3H), 7.34-7.24 (m, 3H), 4.33 (s, 2H), 3.89 (d, J=13.1 Hz,1H), 3.65-3.55 (m, 1H), 3.51-3.40 (m, 2H), 3.40-3.25 (m, 2H), 3.22-3.14(m, 1H), 3.14-3.05 (m, 1H), 2.94-2.80 (m, 1H), 2.39-2.33 (m, 1H),2.14-2.0 (m, 1H), 1.76-1.60 (m, 1H).

Example 1395-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.5; m/z found, 395.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.74 (d, J=7.5 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H),7.43-7.35 (m, 3H), 7.34-7.23 (m, 3H), 4.42-4.32 (m, 2H), 3.65-3.55 (m,4H), 3.33-3.23 (m, 2H), 2.96-2.82 (m, 2H), 2.70-2.63 (m, 2H), 2.55-2.46(m, 2H).

Example 140(R,S)-{3-[4-(Benzothiazol-2-yloxy)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-urea

MS (ESI): mass calcd. C₂₀H₂₀N₄O₂S₂ 380.1; m/z found, 381.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 7.74 (d, J=7.6 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H),7.39 (t, J=7.5 Hz, 1H), 7.36-7.25 (m, 5H), 4.74 (s, 2H), 4.70 (s, 1H),3.59 (s, 2H), 3.09 (d, J=9.0 Hz, 1H), 2.88 (s, 1H), 2.45 (d, J=8.8 Hz,2H), 1.63 (s, 2H).

Example 141(±)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.16; m/z found, 409.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃, mixture of rotamers): 7.74 (d, J=8.1 Hz, 1H),7.67 (d, J=7.9 Hz, 1H), 7.41-7.35 (m, 3H), 7.34-7.22 (m, 3H), 4.38 (s,2H), 3.65-3.26 (m, 5.5H), 2.73-2.29 (m, 4H), 2.24 (s, 2H), 1.82-1.52 (m,2.5H).

Example 142A and Example 142B(+)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylicacid amide and(−)-5-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridine-2-carboxylicacid amide

Individual enantiomers were isolated through preparative chiralsupercritical fluid chromatography (SFC) using isocratic conditions:60:40 carbon dioxide (flow rate: 12 g/min)/(1:1 CH₃CN/isopropanol with0.1% triethylamine; flow rate: 8 mL/min) on a Chiralpak AD-H (5 μm,21×250 mm) column with the back pressure regulator set at 150 bar.Enantiomer 1 (Example 142A): retention time=84 min. MS (ESI): masscalcd. for C₂₂H₂₄N₄O₂S, 408.16; m/z found, 409.2 [M+H]⁺. ¹H NMR (500MHz, 1% CD₃OD/CDCl₃): 7.70 (d, J=8.1 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H),7.46-7.35 (m, 3H), 7.46-7.35 (m, 2H), 7.28-7.22 (m, 1H), 3.79-3.54 (m,3H), 3.23-3.03 (m, 2H), 2.99-2.83 (m, 2H), 2.24-1.79 (m, 4H), 1.56 (s,2H), 1.32-1.18 (m, 2H), 0.92-0.78 (m, 1H). Enantiomer 2 (Example 142B):retention time=125 min. MS (ESI): mass calcd. for C₂₂H₂₄N₄O₂S, 408.16;m/z found, 409.2 [M+H]⁺. ¹H NMR (500 MHz, 1% CD₃OD/CDCl₃): 7.72 (d,J=7.7 Hz, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.42-7.36 (m, 3H), 7.33-7.28 (m,2H), 7.28-7.25 (m, 1H), 3.73-3.51 (m, 2H), 3.16-2.97 (m, 2H), 2.97-2.83(m, 2H), 2.09 (t, J=10.6 Hz, 1H), 1.96-1.82 (m, 3H), 1.60-1.44 (m, 2H),1.34-1.25 (m, 1H), 1.24 (br s, 2H), 0.94-0.78 (m, 1H).

Example 1432-[4-(Benzothiazol-2-yloxy)-benzyl]-octahydro-pyrrolo[3,4-c]pyridine-5-carboxylicacid amide

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 408.16; m/z found, 409.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 8.09-7.01 (m, 8H), 4.59-4.06 (m, 8H), 3.80-2.94(m, 4H), 2.96-2.31 (m, 2H), 2.12-1.36 (m, 2H).

Example 1445-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

Step A: [4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-methanol. A mixtureof 2-chloro-5-fluorobenzothiazole (2.2 g, 12.0 mmol), 4-hydroxylbenzylalcohol (1.48 g, 12.0 mmol) and Cs₂CO₃ (8.6 g, 26.4 mmol) in DMF (30 mL)was stirred at rt overnight. The reaction was filtered and diluted withCH₂Cl₂ (200 mL) and concentrated. The crude mixture was purified viasilica gel column chromatography (1% to 15% CH₃OH/CH₂Cl₂) to afford thetitle compound (1.1 g, 34%). MS (ESI): Mass calcd for C₁₄H₁₀NO₂SF,275.0; m/z found, 276.1 [M+H]⁺.

Step B: 2-(4-Chloromethyl-phenoxy)-6-fluoro-benzothiazole. To a solutionof [4-(6-fluoro-benzothiazol-2-yloxy)-phenyl]-methanol (1.1 g, 4.0 mmol)in CH₂Cl₂ (80 mL) at rt under N₂ was added SOCl₂ (320 μL, 4.4 mmol). Theresultant mixture was stirred for 4 h at rt before concentration toafford the title chloride (1.1 g, 92%). MS (ESI): Mass calcd forC₁₄H₉NOSFCl, 293.0.1; m/z found, 294.1 [M+H]⁺.

Step C: Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amidehydrochloride. This compound was prepared using methods analogous tothose described for Example 76, Step D. MS (ESI): Mass calcd forC₇H₁₃N₃O (free base), 155.11; m/z found, 156.2 [M+H]⁺.

Step D:5-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide. To a suspension of2-(4-chloromethyl-phenoxy)-6-fluoro-benzothiazole (152 mg, 0.52 mmol),hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide hydrochloride(110 mg, 0.57 mmol) and Cs₂CO₃ (676 mg, 2.08 mmol) in DMF (1 mL) wasstirred at rt overnight. The resultant mixture was filtered and theresidue purified via preparative reverse phase HPLC to afford the titlecompound (15 mg, 7%). MS (ESI): Mass calcd for C₂₁H₂₁N₄O₂SF, 412.1; m/zfound, 413.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 7.64 (dd, J=8.9, 4.7 Hz,1H), 7.58 (dd, J=8.4, 2.6 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.33 (d,J=8.5 Hz, 2H), 7.19 (dt, J=9.0, 8.9, 2.6 Hz, 1H), 3.66 (s, 2H),3.59-3.40 (m, 2H), 3.29-3.27 (m, 2H), 2.97-2.83 (m, 2H), 2.77 (d, J=9.3,6.8 Hz, 2H), 2.46 (d, J=9.3, 3.6 Hz, 2H).

Example 1455-[4-(6-Methyl-benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

This compound was prepared using methods analogous to those describedfor Example 144. MS (ESI): Mass calcd for C₂₂H₂₄N₄O₂S, 408.5; m/z found,409.1 [M+H]⁺; ¹H NMR (400 MHz, CD₃OD): 7.47 (d, J=8.6 Hz, 1H), 7.34-7.28(m, 2H), 7.17-7.10 (m, 2H), 6.77-6.65 (m, 2H), 5.05 (s, 2H), 3.58-3.41(m, 2H), 2.96-2.84 (m, 2H), 2.82-2.69 (m, 2H), 2.50-2.38 (m, 4H), 2.34(s, 3H).

Example 1465-{2-[4-(4-Methyl-benzothiazol-2-yloxy)-phenyl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

Step A: 2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenyl]-ethanol. To asolution of phenethyl alcohol (3.15 g, 22.86 mmol) and K₂CO₃ (5.26 g,38.1 mmol) in CH₃CN (35 mL) was added 2-chloro-6-methylbenzothiazole(3.5 g, 19.1 mmol). The reaction mixture was heated at 80° C. for 16 h.To the reaction mixture was added 1 N NaOH (30 mL) and isopropyl acetate(40 mL). The layers were separated and the aqueous layer was extractedwith isopropyl acetate (2×30 mL). The combined organic layers were dried(Na₂SO₄), filtered and concentrated. The resulting residue was purifiedby silica gel flash chromatography (20% to 90% EtOAc in hexanes) toafford the title compound (3.4 g, 63%). ¹H NMR (500 MHz, CDCl₃): 7.61(d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.33-7.28 (m, 4H), 7.20 (d, J=8.3 Hz,1H), 3.87 (br s, 2H), 2.90 (t, J=6.6 Hz, 2H), 2.44 (s, 3H).

Step B: 2-[4-(2-Methanesulfonyl-ethyl)-phenoxy]-6-methyl-benzothiazole.To a solution of 2-[4-(6-methyl-benzothiazol-2-yloxy)-phenyl]-ethanol(6.8 g, 23.8 mmol) and dimethylaminopyridine (290 mg, 2.4 mmol) inCH₂Cl₂ (80 mL) was added (i-Pr)₂NEt (4.9 g, 28.6 mmol) followed by theaddition of methanesulfonyl chloride (2.2 mL, 28.6 mmol) at 0° C. Thereaction was warmed to rt and stirred for 15 min. The reaction waswashed with satd. aq. Na₂CO₃ (75 mL), 5% aq. H₂SO₄ (75 mL) and brine.The organic layer was dried (Na₂SO₄), filtered and concentrated toafford the title compound (7.3 g, 85%). ¹H NMR (500 MHz, CDCl₃): 7.61(d, J=8.3 Hz, 1H), 7.47 (s, 1H), 7.36-7.29 (m, 4H), 7.20 (dd, J=8.3, 1.2Hz, 1H), 4.45 (t, J=6.8 Hz, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.91 (s, 3H),2.44 (s, 3H).

Step C:5-{2-[4-(4-Methyl-benzothiazol-2-yloxy)-phenyl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide. A solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide hydrochloride in 50% CH₂Cl₂/CH₃OH was treated with DOWEXMonosphere 550A (OH) anion-exchange resin to afford the free base. TheDOWEX resin was filtered and the resulting solution was concentrated andused without further purification. To a solution of thishexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid amide (85 mg, 0.54mmol) and K₂CO₃ (116 mg, 0.84 mmol) in tert-amyl alcohol (2.6 mL) wasadded 2-[4-(2-methanesulfonyl-ethyl)-phenoxy]-6-methyl-benzothiazole(120 mg, 0.34 mmol). The reaction mixture was heated to 80° C. for 16 h.The reaction mixture was filtered and washed with CH₃OH. The resultingliquid was purified by preparative reverse phase HPLC to afford thetitle compound (11 mg, 5%). MS (ESI): mass calcd. for C₂₃H₂₆N₄O₂S,422.55; m/z found, 423.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.62 (d, J=8.3Hz, 1H), 7.48 (s, 1H), 7.28 (s, 4H), 7.20 (dd, J=8.3, 1.1 Hz, 1H), 4.39(s, 2H), 3.60 (dd, J=10.2, 8.2 Hz, 2H), 3.30 (dd, J=10.0, 1.9 Hz, 2H),2.98-2.87 (m, 2H), 2.86-2.80 (m, 2H), 2.76 (dd, J=9.3, 6.9 Hz, 2H),2.74-2.67 (m, 2H), 2.53 (dd, J=9.3, 3.4 Hz, 2H), 2.45 (s, 3H).

Example 1475-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

This compound was prepared using methods analogous to those describedfor Example 146. MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₂S, 426.52; m/zfound, 427.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.46 (dd, J=7.9, 1.0 Hz,1H), 7.30 (s, 4H), 7.26-7.21 (m, 1H), 7.16-7.11 (m, 1H), 4.37 (s, 2H),3.61 (dd, J=10.1, 8.2 Hz, 2H), 3.29 (d, J=8.5 Hz, 2H), 2.95-2.88 (m,2H), 2.86-2.81 (m, 2H), 2.79-2.67 (m, 4H), 2.55 (dd, J=9.2, 3.1 Hz, 2H).

Example 1481-(5-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenyl]-ethyl}-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-ethanone

This compound was prepared using methods analogous to those describedfor Example 146, substituting the appropriate amine. MS (ESI): masscalcd. for C₂₄H₂₇N₃O₂S, 421.57; m/z found, 422.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.63 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.28 (s, 4H), 7.21(dd, J=8.3, 1.5 Hz, 1H), 3.70 (ddd, J=16.1, 11.6, 8.6 Hz, 2H), 3.48 (dd,J=12.5, 4.2 Hz, 1H), 3.35 (dd, J=10.8, 4.5 Hz, 1H), 2.99-2.91 (m, 1H),2.90-2.80 (m, 3H), 2.79-2.68 (m, 4H), 2.57-2.50 (m, 2H), 2.45 (s, 3H),2.06 (s, 3H).

Example 1491-[5-(4-Benzothiazol-2-ylmethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethanone

This compound was prepared using methods analogous to those describedfor Example 4. MS (ESI): mass calcd. for C₂₃H₂₅N₃OS, 391.54; m/z found,392.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.01 (d, J=8.0 Hz, 1H), 7.81 (d,J=8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.28 (m, 5H), 4.44 (br s, 2H),3.73-3.62 (m, 2H), 3.59 (dd, J=16.0, 3.0 Hz, 2H), 3.43 (dd, J=16.0, 3.0Hz, 1H), 3.32 (dd, J=16.0, 4.5 Hz, 1H), 2.91-2.87 (m, 1H), 2.84-2.80 (m,1H), 2.65-2.61 (m, 2H), 2.50-2.44 (m, 2H), 2.05 (s, 3H).

Example 1502-[4-(5-Methanesulfonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzyl]-benzothiazole

This compound was prepared using methods analogous to those describedfor Example 4 and Example 45. MS (ESI): mass calcd. for C₂₂H₂₅N₃OS₂,427.59; m/z found, 428.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.01 (d, J=8.0Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.28 (m, 5H),4.44 (s, 2H), 3.59 (s, 2H), 3.49-3.45 (m, 2H), 3.09 (dd, J=9.5, 4.3 Hz,2H), 2.90-2.86 (m, 2H), 2.85 (s, 3H), 2.63 (dd, J=9.5, 6.5 Hz, 2H), 2.44(dd, J=9.5, 3.5 Hz, 2H).

Example 1511-[5-(4-Benzothiazol-2-ylmethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-ethanone

This compound was prepared using methods analogous to those describedfor Example 4 and Example 32. MS (ESI): mass calcd. for C₂₂H₂₄N₄OS,392.53; m/z found, 393.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.01 (d, J=8.3Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.48-7.45 (m, 1H), 7.37-7.29 (m, 5H),4.44 (s, 2H), 4.34 (s, 2H), 3.61-3.58 (m, 4H), 3.27 (dd, J=10.5, 3.5 Hz,2H), 2.90-2.87 (m, 2H), 2.65 (dd, J=9.5, 6.8 Hz, 2H), 2.48 (dd, J=9.5,3.0 Hz, 2H).

Example 152N-{8-[2-(4-Benzothiazol-2-ylmethyl-phenoxy)-ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

This compound was prepared using methods analogous to those describedfor Example 9, Step A. MS (ESI): mass calcd. for C₂₅H₂₉N₃O₂S, 435.20;m/z found, 436.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.98 (d, J=8.0 Hz,1H), 7.77 (d, J=8.0 Hz, 1H), 7.47-7.40 (m, 1H), 7.35-7.23 (m, 3H),6.92-6.83 (m, 2H), 5.88 (d, J=6.2 Hz, 1H), 4.36 (s, 2H), 4.11-4.01 (m,3H), 3.35-3.23 (m, 2H), 2.75 (t, J=6.2 Hz, 2H), 2.25-2.17 (m, 2H),2.16-2.03 (m, 2H), 1.95 (s, 3H), 1.79-1.71 (m, 2H), 1.62-1.54 (m, 2H)

Example 1534-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzoicacid methyl ester

To a solution of2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazole(200 mg, 0.56 mmol) in CH₂Cl₂ (22 mL) was added 4-formyl-benzoic acidmethyl ester (103 mg, 0.62 mmol) followed by the addition of acetic acid(28 μL, 0.48 mmol) then sodium triacetoxyborohydride (144 mg, 0.68mmol). The reaction stirred at rt for 16 h. The reaction was then washedwith satd. aq. NaHCO₃ (2×20 mL). The organic layer was dried, filteredand concentrated. The resulting oil was purified by columnchromatography (20% to 60% EtOAc in Hexanes) to afford the titlecompound (55 mg, 19%). MS (ESI): mass calcd. for C₂₉H₂₉N₃O₃S, 499.64;m/z found, 500.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.01 (d, J=8.3 Hz,2H), 7.76 (d, J=8.1 Hz, 1H), 7.47-7.38 (m, 1H), 7.35-7.26 (m, 4H), 7.68(d, J=7.9 Hz, 4H), 3.92 (s, 4H), 3.65 (d, J=12.2 Hz, 4H), 2.71-2.60 (m,3H), 2.38 (d, J=7.2 Hz, 4H), 1.27 (s, 2H).

Example 1544-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzoicacid

To a solution of4-{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzoicacid methyl ester (58.5 mg, 0.12 mmol, 1 equiv) in isopropanol (2.5 mL)was added water (1.1 mL) followed by the addition of aq. KOH (13 mg in2.5 mL water). The reaction stirred at rt for 16 h. The reaction mixturewas acidified to pH 6 with 6 N HCl, and CH₂Cl₂ was added. The layerswere separated and the aqueous layer was extracted with 25%isopropanol/CH₂Cl₂ (2×10 mL). The combined organics were dried, filteredand concentrated to afford the title compound (32 mg, 56%). MS (ESI):mass calcd. for C₂₈H₂₇N₃O₃S, 485.61; m/z found, 486.2 [M+H] ⁺. ¹H NMR(500 MHz, CDCl₃): 8.01 (d, J=8.2 Hz, 2H), 7.71 (m, 2H), 7.52-7.44 (m,4H), 7.43-7.34 (m, 4H), 3.95 (m, 4H), 3.13 (s, 3H), 2.81 (m, 5H), 2.03(s, 1H), 1.27 (s, 2H).

The compounds in Examples 155-157 were prepared using methods analogousto those described in Example 50.

Example 155{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-aceticacid ethyl ester

MS (ESI): Mass calcd for C₂₄H₂₇N₃O₃S, 437.6; m/z found, 438.2 [M+H]⁺; ¹HNMR (500 MHz, CD₃OD): 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H),7.52-7.46 (m, 2H), 7.46-7.39 (m, 1H), 7.37-7.29 (m, 3H), 4.19 (q, J=7.1Hz, 2H), 3.67 (s, 2H), 3.32 (s, 2H), 2.88-2.81 (m, 2H), 2.81-2.71 (m,2H), 2.71-2.63 (m, 2H), 2.53-2.40 (m, 4H), 1.28 (t, J=7.1 Hz, 3H).

Example 1564-{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-butyricacid methyl ester

MS (ESI): Mass calcd for C₂₅H₂₉N₃O₃S, 451.6; m/z found, 452.2 [M+H]⁺; ¹HNMR (500 MHz, CD₃OD): 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H),7.51-7.46 (m, 2H), 7.45-7.39 (m, 1H), 7.37-7.28 (m, 3H), 3.69-3.63 (m,5H), 2.78-2.70 (m, 4H), 2.69-2.59 (m, 2H), 2.52-2.41 (m, 4H), 2.43-2.30(m, 4H), 1.90-1.72 (m, 2H).

Example 157{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-aceticacid methyl ester

MS (ESI): Mass calcd for C₂₃H₂₅N₃O₃S, 423.5; m/z found, 424.2 [M+H]⁺. ¹HNMR (CD₃OD): 7.81-7.76 (m, 1H), 7.66-7.60 (m, 2H), 7.56-7.49 (m, 2H),7.45-7.40 (m, 1H), 7.38-7.33 (m, 2H), 4.92 (s, 2H), 4.57 (s, 2H),4.48-4.36 (m, 2H), 3.77 (s, 3H), 3.57-3.47 (m, 2H), 3.25-3.17 (m, 2H),2.95-2.86 (m, 2H), 2.47-2.35 (m, 2H).

Example 158{5-[4-(Benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-aceticacid

A solution of{5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-aceticacid methyl ester (233 mg, 0.55 mmol) in 1:1 isopropanol/water (2 mL)was treated with KOH (62 mg, 1.1 mmol). The reaction stirred at rtovernight. The reaction was acidified to pH 6.5 and extracted with 25%isopropanol/CHCl₃ to afford pure acid as a white powder (67 mg, 30%). MS(ESI): Mass calcd for C₂₂H₂₃N₃O₃S, 409.5; m/z found, 410.2 [M+H]⁺; ¹HNMR (400 MHz, CD₃OD): 7.78 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H),7.57 (d, J=8.6 Hz, 2H), 7.45-7.35 (m, 3H), 7.34-7.28 (m, 1H), 3.76 (s,2H), 3.64 (s, 2H), 3.55-3.35 (m, 4H), 3.12-2.97 (m, 2H), 2.94 (d, J=9.9Hz, 2H), 2.52-2.34 (m, 2H).

The compounds in Examples 159-161 were prepared using methods analogousto those described in Example 76.

Example 1595-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂S, 412.1; m/z found, 413.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.75 (dd, J=8.1, 0.6 Hz, 1H), 7.70 (dd, J=8.0,0.7 Hz, 1H), 7.42 (m, 2H), 7.33-7.27 (m, 1H), 7.18-7.10 (m, 2H), 4.31(s, 2H), 3.68 (s, 2H), 3.65-3.54 (m, 2H), 3.27 (dd, J=10.3, 3.6 Hz, 2H),2.92-2.85 (m, 2H), 2.77-2.65 (m, 2H), 2.53 (dd, J=9.3, 3.2 Hz, 2H).

Example 160meso-endo-N-{8-[2-Fluoro-4-(4-fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₀H₂₃F₂N₃O₂S, 443.1; m/z found, 444.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.64 (t, J=8.4 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.29-7.09 (m, 4H), 5.81-5.73 (m, 1H), 4.17-4.06 (m, 1H), 3.56 (s, 2H),3.22 (s, 2H), 2.40-2.02 (m, 4H), 1.97 (s, 3H), 1.88-1.70 (m, 2H), 1.62(d, J=14.8 Hz, 2H).

Example 1615-[2-Fluoro-4-(4-fluoro-benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₀F₂N₄O₂S, 430.1; m/z found, 431.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.46 (t, J=8.6 Hz, 1H), 7.21-7.08 (m, 2H),7.30-7.21 (m, 3H), 4.33 (s, 2H), 3.86 (d, J=6.6 Hz, 1H), 3.66-3.55 (m,2H), 3.32-3.22 (m, 2H), 3.06-2.84 (m, 2H), 2.78-2.65 (m, 1H), 2.62-2.45(m, 1H), 0.94 (d, J=6.7 Hz, 3H).

The compounds in examples 162-284 were prepared using methods analogousto those described in the preceding examples, replacing theappropriately substituted 2-[4-(2-bromo-ethyl)-phenoxy]-benzothiazoleintermediate with its 2-[4-(2-iodo-ethyl)-phenoxy]-benzothiazole analogwhere A is an ethylene group.

Example 162meso-exo-N-(8-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₃S₂, 491.11; m/z found, 492.15[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.57-7.53 (m, 1H), 7.44-7.41 (m, 1H),7.33-7.26 (m, 4H), 7.23-7.17 (m, 1H), 3.60-3.80 (m, 3H), 3.00-3.15 (m,2H), 3.04 (s, 3H), 2.80-2.94 (m, 2H), 1.96-2.25 (m, 6H), 1.78-1.90 (m,2H).

Example 163meso-exo-N-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₂S, 455.14; m/z found, 456.15[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 8.14-8.07 (m,0.8H), 8.00-7.94 (m, 0.6H), 7.70-7.65 (m, 1H), 7.51-7.31 (m, 4.6H),4.15-3.90 (m, 2.4H), 3.23-3.05 (m, 3H), 2.32-2.19 (m, 1.6H), 2.04-1.86(m, 4.6H), 1.85-1.71 (m, 3.3H), 1.64-1.42 (m, 0.6H).

Example 164(R,R)-1-{5-[4-(4-Chloro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₁H₂₀ClN₃O₂S, 413.10; m/z found, 414.15[M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.52-7.61 (m, 1H),7.30-7.60 (m, 5H), 7.18-7.30 (m, 1H), 4.79 (s, 0.5H), 4.25 (s, 0.5H),3.74-3.82 (m, 2.5H), 3.55-3.63 (m, 1.5H), 3.24-3.40 (m, 1H), 3.01-3.05(m, 0.5H), 2.76-2.87 (m, 1H), 2.55-2.58 (m, 0.5H), 1.98-2.05 (m, 3.5H),1.64-1.97 (m, 1.5H).

Example 165meso-exo-1-{3-[4-(5-Fluoro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄FN₃O₂S, 425.16; m/z found, 426.15[M+H]⁺. ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d₆): 8.03-7.97 (m, 1H),7.60-7.53 (m, 3H), 7.50-7.44 (m, 2H), 7.28-7.21 (m, 1H), 4.53-4.43 (m,1H), 4.30-4.24 (m, 1H), 4.06-3.90 (m, 2H), 2.10-2.02 (m, 1H), 2.01-1.89(m, 6H), 1.88-1.75 (m, 1H), 1.74-1.66 (m, 1H), 1.66-1.46 (m, 3H).

Example 166meso-exo-1-{3-[4-(7-Chloro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₂S, 441.13; m/z found, 442.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.74-7.66 (m, 1H), 7.52-7.45 (m, 4H),7.44-7.39 (m, 2H), 4.45-4.41 (m, 1H), 4.21-4.15 (m, 1H), 3.76 (s, 2H),3.06-2.94 (m, 1H), 2.01-1.88 (m, 5H), 1.88-1.81 (m, 1H), 1.80-1.71 (m,1H), 1.70-1.62 (m, 1H), 1.62-1.54 (m, 1H), 1.38-1.28 (m, 2H).

Example 167meso-endo-N-{8-[4-(4-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₃S₂, 477.09; m/z found, 478.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.91 (d, J=8.0 Hz, 1H), 7.54 (d,J=7.8 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.33 (t,J=8.0 Hz, 1H), 6.71-6.67 (m, 1H), 3.57-3.45 (m, 3H), 3.12-3.00 (m, 2H),2.91-2.83 (m, 3H), 2.08-1.87 (m, 6H), 1.78-1.70 (m, 2H)

Example 168(R,R)-5-Fluoro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂FN₃O₄S₂, 463.10; m/z found, 464.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.98-7.93 (m, 1H), 7.60-7.54 (m, 1H),7.42-7.36 (m, 2H), 7.24-7.18 (m, 1H), 7.09-7.04 (m, 2H), 4.19-4.14 (m,1H), 4.10-4.04 (m, 2H), 3.68-3.62 (m, 1H), 3.23-3.16 (m, 1H), 3.00-2.88(m, 6H), 2.74-2.66 (m, 1H), 1.81-1.74 (m, 1H), 1.70-1.63 (m, 1H).

Example 169meso-6-Chloro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₄S₂, 493.09; m/z found, 494.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.09-8.06 (m, 1H), 7.70-7.66 (m, 1H),7.48-7.43 (m, 1H), 7.41-7.36 (m, 2H), 7.10-7.04 (m, 2H), 4.14-4.03 (m,2H), 3.46-3.40 (m, 2H), 3.19-3.11 (m, 2H), 2.99-2.90 (m, 2H), 2.84 (s,3H), 2.75-2.70 (m, 2H), 1.99-1.81 (m, 2H), 1.67-1.59 (m, 2H).

Example 170(S,S)-1-{5-[4-(5-Fluoro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₂S, 397.13; m/z found, 398.10[M+H]⁺. ¹H NMR (500 MHz, CDCl₃, mixture of rotamers): 7.62-7.55 (m, 1H),7.55-7.35 (m, 3H), 7.35-7.22 (m, 2H), 7.05-6.96 (m, 1H), 4.81-4.75 (m,0.5H), 4.20-4.25 (m, 0.5H), 3.82-3.70 (m, 2H), 3.64-3.50 (m, 1.5H),3.38-3.21 (m, 1H), 3.03-2.98 (m, 0.5H), 2.85-2.75 (m, 1.5H), 2.80-2.52(m, 0.5H), 2.06-1.96 (m, 3H), 2.00-1.63 (m, 2H).

Example 171meso-endo-3-[4-(7-Fluoro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₂S, 426.15; m/z found, 427.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.72-7.61 (m, 2H), 7.60-7.55 (m, 2H),7.53-7.47 (m, 1H), 7.33-7.26 (m, 1H), 6.11 (s, 1H), 4.28-4.12 (m, 4H),3.71-3.54 (m, 1H), 2.02-1.82 (m, 4H), 1.79-1.68 (m, 2H), 1.66-1.59 (m,2H).

Example 172meso-exo-1-(3-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₅H₂₉N₃O₃S, 451.19; m/z found, 452.10 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.71-7.69 (m, 1H), 7.55 (d, J=8.2 Hz, 1H),7.36 (d, J=8.9 Hz, 2H), 7.25-7.21 (m, 1H), 7.06 (d, J=9.0 Hz, 2H),4.42-4.32 (m, 1H), 4.14-4.00 (m, 3H), 3.02-2.80 (m, 3H), 2.38 (s, 3H),2.20-2.03 (m, 2H), 1.94 (s, 3H), 1.91-1.59 (m, 7H).

Example 173meso-exo-3-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₄H₂₅N₄O₂S, 436.19; m/z found, 437.25 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H),7.42-7.36 (m, 4H), 7.27-7.22 (m, 1H), 6.03 (br s, 2H), 4.17 (br s, 2H),3.14-2.96 (m, 2H), 2.93-2.84 (m, 2H), 2.39 (s, 3H), 1.91-1.79 (m, 4H),1.66-1.50 (m, 4H).

Example 174meso-7-Chloro-2-[4-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂ClN₃O₃S₂, 463.08; m/z found, 464.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.73-7.68 (m, 1H), 7.56-7.42 (m, 6H),3.57 (s, 2H), 3.28-3.23 (m, 2H), 3.22-3.18 (m, 2H), 2.99-2.93 (m, 2H),2.87-2.85 (m, 3H), 2.03-1.95 (m, 2H), 1.70-1.62 (m, 2H).

Example 175meso-endo-1-{3-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄FN₃O₂S, 425.16; m/z found, 426.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.86 (dd, J=8.7, 2.7 Hz, 1H), 7.70 (dd,J=8.9, 4.9 Hz, 1H), 7.48-7.45 (m, 2H), 7.40-7.37 (m, 2H), 7.31-7.26 (m,1H), 4.40-4.34 (m, 1H), 4.15-4.07 (m, 1H), 3.77-3.72 (m, 2H), 2.94-2.86(m, 1H), 2.31-2.13 (m, 3H), 1.94 (s, 3H), 1.86-1.67 (m, 5H).

Example 176(R,R)-5-{2-[4-(5-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁ClN₄O₃S, 444.10; m/z found, 445.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.95 (d, J=8.6 Hz, 1H), 7.77 (d,J=2.1 Hz, 1H), 7.40-7.35 (m, 3H), 7.09-7.03 (m, 2H), 5.80-5.70 (m, 2H),4.27-4.20 (m, 1H), 4.10-4.00 (m, 2H), 3.60-3.52 (m, 1H), 3.30-3.24 (m,1H), 3.10-3.03 (m, 1H), 2.94-2.85 (m, 3H), 2.57-2.52 (m, 1H), 1.77-1.57(m, 2H).

Example 177(R,R)-1-(5-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂ClN₃O₃S, 443.11; m/z found, 444.1[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.32-8.30 (m, 1H), 8.07 (d, J=2.2 Hz,1H), 7.70-7.65 (m, 1H), 7.47-7.43 (m, 1H), 7.39-7.36 (m, 1.5H),7.07-7.04 (m, 1.5H), 4.53-4.31 (m, 1H), 4.13-3.99 (m, 2H), 3.71-3.55 (m,1H), 3.55-3.39 (m, 1H), 3.15-2.84 (m, 3H), 2.52-2.50 (m, 3H), 1.97 (s,1H), 1.86 (s, 1H), 1.83-1.55 (m, 2H).

Example 178meso-exo-1-(3-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₃S, 471.14; m/z found, 472.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.09-8.05 (m, 1H), 7.68 (d, J=8.7 Hz,1H), 7.45 (dd, J=8.7, 2.3 Hz, 1H), 7.40-7.35 (m, 2H), 7.07-7.03 (m, 2H),5.75 (s, 1H), 4.46-4.40 (m, 1H), 4.22-4.15 (m, 1H), 4.07-3.98 (m, 2H),3.09-2.97 (m, 1H), 2.94-2.87 (m, 2H), 1.98-1.93 (m, 4H), 1.89-1.61 (m,5H), 1.33-1.22 (m, 2H).

Example 179meso-exo-(8-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₂S, 440.17; m/z found, 441.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.86 (dd, J=8.7, 2.7 Hz, 1H), 7.70 (dd,J=8.9, 4.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.36-7.32 (m, 2H), 7.31-7.26 (m,1H), 5.80-5.71 (m, 1H), 5.27 (s, 2H), 3.72-3.60 (m, 1H), 3.29-3.18 (m,2H), 2.79-2.70 (m, 2H), 2.61-2.53 (m, 2H), 1.93-1.82 (m, 2H), 1.63-1.49(m, 4H), 1.44-1.33 (m, 2H).

Example 180(R,R)-1-(5-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₃H₂₅N₃O₃S, 423.16; m/z found, 424.2 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.72-7.68 (m, 1H), 7.55 (d, J=8.3 Hz, 1H),7.37-7.34 (m, 2H), 7.26-7.21 (m, 1H), 7.06-7.02 (m, 2H), 4.54-4.31 (m,1H), 4.12-4.00 (m, 2H), 3.71-3.40 (m, 3H), 3.12-2.85 (m, 3H), 2.66-2.53(m, 1H), 2.38 (s, 3H), 2.00-1.85 (m, 3H), 1.84-1.57 (m, 2H).

Example 181(R,R)-5-Chloro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀ClN₃O₃S₂, 449.06; m/z found, 450.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.97 (d, J=8.6 Hz, 1H), 7.80-7.78 (m,1H), 7.50-7.47 (m, 2H), 7.42-7.37 (m, 3H), 4.21-4.16 (m, 1H), 3.83-3.74(m, 2H), 3.57-3.50 (m, 1H), 3.45-3.41 (m, 1H), 3.24-3.19 (m, 1H), 2.95(s, 3H), 2.82-2.77 (m, 1H), 2.65-2.60 (m, 1H), 2.55-2.51 (m, 2H).

Example 182(S,S)-7-Chloro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂ClN₃O₄S₂, 479.07; m/z found, 480.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.69 (dd, J=7.8, 1.2 Hz, 1H),7.51-7.43 (m, 2H), 7.43-7.39 (m, 2H), 7.10-7.05 (m, 2H), 4.17-4.15 (m,1H), 4.09-4.05 (m, 2H), 3.66-3.63 (m, 1H), 3.21-3.16 (m, 1H), 2.94-2.91(m, 4H), 2.73-2.68 (m, 1H), 2.51-2.50 (m, 3H), 1.81-1.73 (m, 1H),1.69-1.62 (m, 1H).

Example 183(R,R)-1-{5-[4-(5-Fluoro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₂S, 397.13; m/z found, 398.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.97 (dd, J=8.8, 5.5 Hz, 1H), 7.59-7.55 (m,1H), 7.50-7.45 (m, 2H), 7.41-7.37 (m, 2H), 7.25-7.19 (m, 1H), 4.57-4.33(m, 1H), 3.82-3.73 (m, 2H), 3.63-3.43 (m, 3H), 3.18-3.07 (m, 1H),2.87-2.76 (m, 1H), 1.97 (s, 1H), 1.92-1.86 (m, 2H), 1.86-1.59 (m, 2H).

Example 184meso-exo-1-{3-[4-(6-Methyl-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone

MS (ESI): mass calcd. for C₂₄H₂₇N₃O₂S, 421.18; m/z found, 422.2 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.73-7.70 (m, 1H), 7.56 (d, J=8.2 Hz, 1H),7.47-7.43 (m, 2H), 7.38-7.34 (m, 2H), 7.26-7.22 (m, 1H), 4.46-4.39 (m,1H), 4.21-4.17 (m, 1H), 3.80-3.71 (m, 2H), 3.09-2.97 (m, 1H), 2.39 (s,3H), 1.98-1.94 (m, 4H), 1.93-1.71 (m, 3H), 1.70-1.54 (m, 2H), 1.37-1.28(m, 2H).

Example 185meso-exo-[4-(5-Chloro-benzothiazol-2-yloxy)-benzyl]-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₃S₂, 477.09; m/z found, 478.0[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.97 (d, J=8.6 Hz, 1H), 7.79-7.77 (m,1H), 7.50-7.45 (m, 2H), 7.41-7.37 (m, 3H), 4.17-4.07 (m, 2H), 3.80-3.73(m, 2H), 2.99-2.87 (m, 4H), 2.00-1.93 (m, 4H), 1.68-1.61 (m, 2H),1.49-1.39 (m, 2H).

Example 186(R,R)-5-[4-(4-Fluoro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₀H₁₉FN₄O₂S, 398.12; m/z found, 399.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.79-7.75 (m, 1H), 7.51-7.46 (m, 2H),7.44-7.39 (m, 2H), 7.37-7.28 (m, 2H), 5.77 (s, 2H), 4.30-4.23 (m, 1H),3.77-3.70 (m, 2H), 3.49-3.45 (m, 1H), 3.13-3.06 (m, 1H), 2.82-2.73 (m,1H), 1.95-1.89 (m, 1H), 1.84-1.76 (m, 1H), 1.66-1.59 (m, 1H), 1.29-1.19(m, 1H).

Example 187meso-endo-N-(8-{2-[4-(7-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₂S, 456.01; m/z found, 457.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.69 (d, J=7.7 Hz, 1H), 7.49-7.39 (m,6H), 4.28 (br s, 1H), 4.10 (br s, 1H), 2.90-2.78 (m, 5H), 2.07-1.92 (m,6H), 1.85-1.78 (br m, 3H), 1.68-1.55 (m, 3H).

Example 188meso-exo-N-{8-[4-(4-Fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₃S₂, 461.58; m/z found, 462.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.80 (d, J=7.8 Hz, 1H), 7.50-7.26 (m,5H), 7.00 (br s, 1H), 3.59 (br s, 2H), 3.17 (br s, 2H), 2.91 (br s, 3H),2.00 (br s, 3H), 1.73-1.62 (br m, 5H).

Example 189(R,R)-7-Fluoro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀FN₃O₃S₂, 433.53; m/z found, 434.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.59 (d, J=8.1 Hz, 1H), 7.51-7.47 (m,3H), 7.44-7.43 (m, 2H), 7.29-7.25 (m, 1H), 4.19 (br s, 1H), 3.82-3.76(m, 2H), 3.55 (br s, 1H), 3.43 (d, J=9.1 Hz, 1H), 3.23-3.21 (m, 1H),2.95 (s, 3H), 2.82-2.80 (m, 1H), 2.65-2.62 (m, 1H), 1.86-1.84 (m, 1H),1.70-1.68 (m, 1H).

Example 190meso-endo-(8-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₂S, 440.54; m/z found, 441.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.59 (d, J=8.1 Hz, 1H), 7.50-7.46 (m, 1H),7.39-7.36 (m, 4H), 7.28-7.24 (m, 1H), 5.90 (d, J=6.6 Hz, 1H), 5.40 (s,2H), 3.68-3.66 (m, 1H), 3.18 (br s, 2H), 2.76-2.73 (m, 2H), 2.00-1.82(m, 6H), 1.48-1.44 (m, 2H).

Example 191(S,S)-4-Fluoro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂FN₃O₄S₂, 463.55; m/z found, 464.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.75 (d, J=7.7 Hz, 1H), 7.42-7.38 (m,2H), 7.34-7.29 (m, 2H), 7.09-7.05 (m, 2H), 4.16 (br s, 1H), 4.08-4.06(m, 2H), 3.65 (br s, 1H), 3.20-3.18 (m, 1H), 2.95-2.90 (m, 6H),2.72-2.70 (m, 1H), 1.78-1.76 (m, 1H), 1.67-1.65 (m, 1H).

Example 192(R,R)-7-Chloro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂ClN₃O₃S₂, 464.01; m/z found, 465.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.71-7.69 (m, 1H), 7.50-7.45 (m, 2H),7.42-7.38 (m, 4H), 4.16 (br s, 1H), 3.58 (br s, 1H), 3.18-3.15 (m, 1H),2.92 (s, 3H), 2.86-2.80 (m, 3H), 2.78-2.70 (m, 3H), 2.67-2.65 (m, 1H),2.76-2.74 (m, 1H), 1.65-1.63 (m, 1H).

Example 193(R,R)-2-{4-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-6-methyl-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₅N₃O₃S₂, 443.59; m/z found, 444.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.71 (br s, 1H), 7.56 (d, J=8.1 Hz, 1H),7.38-7.32 (m, 4H), 7.25-7.23 (m, 1H), 4.16 (br s, 1H), 3.58 (br s, 1H),3.17-3.15 (m, 1H), 2.92 (s, 3H), 2.92-2.65 (m, 6H), 2.39 (s, 3H),1.76-1.74 (m, 1H), 1.65-1.63 (m, 1H).

Example 194meso-endo-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₄S₂, 508.06; m/z found, 509.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.89 (d, J=7.7 Hz, 1H), 7.53 (d,J=7.7 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.34-7.28 (m, 1H), 7.08 (d, J=8.2Hz, 2H), 4.07 (br s, 4H), 2.91 (br s, 6H), 2.15 (br s, 2H), 1.90-1.76(br m, 7H).

Example 195meso-exo-N-(8-{2-[4-(7-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₃S, 472.01; m/z found, 473.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.70-7.65 (m, 2H), 7.50-7.46 (m, 2H),7.44-7.41 (m, 2H), 7.09-7.07 (m, 2H), 4.10-4.08 (m, 2H), 3.92-3.88 (m,1H), 2.78-2.75 (m, 2H), 1.91-1.88 (m, 2H), 1.75 (s, 3H), 1.56-1.50 (m,6H).

Example 196(R,R)-5-[4-(7-Chloro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₀H₁₉ClN₄O₂S, 414.92; m/z found, 415.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.70 (d, J=7.2 Hz, 1H), 7.50-7.44 (m,6H), 5.80 (br s, 2H), 4.28 (br s, 1H), 3.75 (br s, 2H), 3.11 (br s, 1H),2.79 br s, 1H), 1.82 (br s, 1H), 1.65 (br s, 1H).

Example 197meso-endo-1-(3-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₂S, 439.56; m/z found, 440.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.98-7.94 (m, 1H), 7.58-7.55 (m, 1H),7.43-7.35 (m, 4H), 7.24-7.21 (m, 1H), 4.32 (br s, 1H), 4.07 (br s, 1H),2.89 (br s, 1H), 2.79 (br s, 3H), 2.00-1.84 (m, 7H), 1.68-1.57 (m, 3H).

Example 198meso-endo-3-[4-(4-Fluoro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₂S, 426.52; m/z found, 427.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.77 (d, J=7.8 Hz, 1H), 7.50-7.29 (m, 6H),5.85 (br s, 2H), 4.08 (br s, 2H), 3.77 (br s, 1H), 2.90 (br s, 1H),2.20-1.79 (br m, 7H), 1.62-1.59 (m, 2H).

Example 199meso-1-(8-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄FN₃O₃S, 441.53; m/z found, 442.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.95 (dd, J=8.9, 5.5 Hz, 1H), 7.56 (dd,J=9.9, 2.5 Hz, 1H), 7.39-7.36 (m, 2H), 7.23-7.19 (m, 1H), 7.08-7.06 (m,2H), 4.13-4.11 (m, 2H), 3.97-3.94 (m, 1H), 3.46-3.43 (m, 1H), 3.24-3.22(m, 1H), 2.72-2.70 (m, 3H), 1.96 (s, 3H), 1.88-1.83 (m, 2H), 1.58-1.54(m, 1H), 1.41-1.37 (m, 1H).

Example 200meso-exo-N-{8-[4-(6-Methyl-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₇N₃O₃S₂, 457.15; m/z found, 458.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 7.61 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H),7.47 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.20 (dd, J=8.3, 1.1 Hz, 1H), 3.66(s, 3H), 3.37 (s, 2H), 2.97 (s, 3H), 2.43 (s, 3H), 2.17-2.06 (m, 2H),2.03-1.84 (m, 4H), 1.82-1.68 (m, 2H).

Example 201(R,R)-6-Fluoro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀FN₃O₃S₂, 433.09; m/z found, 434.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.87 (d, J=8.7 Hz, 1H), 7.74-7.65 (m,1H), 7.48 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.3 Hz, 2H), 7.29 (t, J=9.1 Hz,1H), 4.18 (s, 1H), 3.85-3.69 (m, 2H), 3.54 (s, 1H), 3.43 (d, J=9.4, 1H),3.27-3.17 (m, 1H), 2.95 (s, 3H), 2.80 (d, J=9.5 Hz, 1H), 2.62 (d, J=9.5Hz, 1H), 1.84 (d, J=9.7 Hz, 1H), 1.68 (d, J=9.9 Hz, 1H).

Example 202meso-exo-(8-{2-[4-(5-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅ClN₄O₂S, 456.14; m/z found, 457.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.98 (d, J=8.6 Hz, 1H), 7.78 (d,J=2.0 Hz, 1H), 7.49-7.18 (m, 5H), 5.97 (s, 1H), 5.37 (s, 2H), 3.66 (s,1H), 3.24 (s, 2H), 2.82-2.69 (m, 2H), 2.60-2.53 (m, 2H), 1.87 (s, 2H),1.64-1.47 (m, 4H), 1.48-1.29 (m, 2H).

Example 203(R,R)-4-Chloro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂ClN₃O₄S₂, 479.07; m/z found, 480.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.89 (dd, J=8.0, 1.1 Hz, 1H), 7.53(dd, J=7.9, 1.1 Hz, 1H), 7.46-7.39 (m, 2H), 7.31 (t, J=8.0 Hz, 1H),7.12-7.04 (m, 2H), 4.16 (s, 1H), 4.11-4.04 (m, 2H), 3.64 (s, 1H), 3.36(d, J=9.3 Hz, 1H), 3.19 (dd, J=9.4, 2.1 Hz, 1H), 3.02-2.86 (m, 6H), 2.71(d, J=9.8 Hz, 1H), 1.77 (d, J=9.9 Hz, 1H), 1.66 (d, J=9.9 Hz, 1H).

Example 204meso-exo-(8-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.79-7.71 (m, 1H), 7.45-7.36 (m, 2H),7.36-7.25 (m, 2H), 7.10-7.02 (m, 2H), 5.90 (d, J=6.8 Hz, 1H), 5.39 (s,2H), 4.07 (t, J=6.1 Hz, 2H), 3.65 (d, J=7.0 Hz, 1H), 3.21 (s, 2H), 2.68(t, J=6.2 Hz, 2H), 2.05-1.73 (m, 6H), 1.46 (d, J=13.8 Hz, 2H).

Example 205meso-exo-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzyl]-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₃S₂, 461.12; m/z found, 462.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.87 (dd, J=8.7, 2.7 Hz, 1H), 7.70(dd, J=8.9, 4.9 Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H),7.29 (td, J=9.1, 2.8 Hz, 1H), 4.13 (s, 2H), 3.74 (s, 2H), 3.41-3.21 (m,1H), 2.93 (s, 3H), 2.03-1.86 (m, 5H), 1.64 (d, J=7.8 Hz, 2H), 1.41 (s,2H).

Example 206(S,S)-5-Chloro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀ClN₃O₃S₂, 449.06; m/z found, 450.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.97 (d, J=8.5 Hz, 1H), 7.79 (s, 1H),7.48 (d, J=8.2 Hz, 2H), 7.44-7.32 (m, 3H), 4.18 (s, 1H), 3.87-3.71 (m,2H), 3.54 (s, 1H), 3.41 (t, J=17.4 Hz, 1H), 3.22 (d, J=8.8 Hz, 1H), 2.94(s, 3H), 2.80 (d, J=8.6 Hz, 1H), 2.62 (d, J=9.5 Hz, 1H), 1.84 (d, J=9.9Hz, 1H), 1.68 (d, J=9.7 Hz, 1H).

Example 207(S,S)-1-{5-[4-(4-Fluoro-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₁H₂₀FN₃O₂S, 397.13; m/z found, 398.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 7.77 (dd, J=7.8, 1.2 Hz,1H), 7.53-7.45 (m, 2H), 7.44-7.39 (m, 2H), 7.40-7.23 (m, 2H), 4.52 (s,0.5H), 4.37 (s, 0.5H), 4.09 (s, 0.5H), 3.78 (d, J=4.4 Hz, 1H), 3.62-3.42(m, 2H), 3.17 (s, 1H), 3.12 (d, J=9.0 Hz, 0.5H), 2.90-2.73 (m, 1H), 2.52(d, J=14.2 Hz, 0.5H), 2.46 (d, J=9.5 Hz, 0.5H), 1.97 (s, 1.5H), 1.87 (d,J=18.5 Hz, 2H), 1.82 (d, J=9.7 Hz, 0.5H), 1.72 (d, J=9.6 Hz, 0.5H), 1.62(d, J=9.6 Hz, 0.5H).

Example 208meso-endo-N-{8-[4-(5-Fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₃S₂, 461.12; m/z found, 462.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.61 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.5Hz, 2H), 7.47 (s, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.20 (dd, J=8.3, 1.1 Hz,1H), 3.66 (s, 3H), 2.97 (s, 3H), 2.43 (s, 3H), 2.16-2.06 (m, 2H), 1.91(dd, J=14.4, 8.1 Hz, 4H), 1.76 (d, J=8.4 Hz, 2H).

Example 209meso-exo-1-(3-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₂S, 439.17; m/z found, 440.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.88 (d, J=6.0 Hz, 1H), 7.70 (dd, J=8.9, 4.9Hz, 1H), 7.38 (s, 4H), 7.29 (s, 1H), 4.43 (s, 1H), 4.20 (s, 1H), 2.94(s, 2H), 2.83 (s, 2H), 1.96 (s, 3H), 1.93-1.52 (m, 6H), 1.40 (s, 2H).

Example 210meso-5-Fluoro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₃S₂, 461.12; m/z found, 462.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.32 (s, 1H), 7.96 (dd, J=8.8, 5.5Hz, 1H), 7.56 (dd, J=9.9, 2.6 Hz, 1H), 7.43-7.32 (m, 3H), 7.22 (td,J=9.1, 2.6 Hz, 1H), 3.38 (s, 2H), 3.16 (s, 2H), 3.01-2.68 (m, 7H),2.62-2.50 (m, 2H), 1.91-1.86 (m, 2H), 1.68-1.56 (m, 2H).

Example 211meso-7-Fluoro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₄S₂, 477.12; m/z found, 478.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.58 (d, J=8.1 Hz, 1H), 7.52-7.46 (m,1H), 7.46-7.38 (m, 2H), 7.29-7.21 (m, 1H), 7.08 (d, J=9.0 Hz, 2H), 4.11(t, J=5.8 Hz, 2H), 3.43 (s, 2H), 3.16 (d, J=8.5 Hz, 2H), 2.94 (d, J=11.2Hz, 3H), 2.84 (s, 2H), 2.73 (t, J=5.8 Hz, 2H), 1.89 (s, 2H), 1.63 (d,J=7.4 Hz, 2H).

Example 212meso-exo-3-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₆N₄O₂SF, 440.2; m/z found, 441.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.59 (d, J=8.1 Hz, 1H), 7.52-7.45 (m, 3H),7.45-7.40 (m, 2H), 7.29-7.23 (m, 1H), 4.07 (s, 2H), 3.76-3.70 (m, 2H),2.91 (s, 3H), 2.26-2.21 (m, 2H), 2.21-2.14 (m, 1H), 1.95-1.88 (m, 2H),1.88-1.80 (m, 4H).

Example 213meso-exo-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆N₃O₄S₂F, 491.1; m/z found, 492.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.75 (d, J=7.3 Hz, 1H), 7.45-7.36 (m, 2H),7.36-7.26 (m, 2H), 7.13-7.01 (m, 2H), 4.43-4.26 (m, 1H), 4.11-4.04 (m,3H), 2.96-2.83 (m, 3H), 2.22-2.02 (m, 2H), 1.94 (s, 3H), 1.90-1.77 (m,4H), 1.75-1.59 (m, 3H).

Example 214meso-2-{4-[2-(3-Methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethyl]-phenoxy}-6-methyl-benzothiazole

MS (ESI): mass calcd. for C₂₃H₂₇N₃O₃S₂, 457.2; m/z found, 458.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.71 (s, 1H), 7.60-7.50 (m, 1H), 7.41-7.35(m, 2H), 7.35-7.30 (m, 2H), 7.26-7.21 (m, 1H), 3.41-3.33 (m, 2H),3.19-3.11 (m, 2H), 2.98-2.89 (m, 2H), 2.88-2.81 (m, 2H), 2.81-2.70 (m,2H), 2.60-2.51 (m, 2H), 2.38 (s, 3H), 1.96-1.77 (m, 2H), 1.67-1.55 (m,2H).

Example 215meso-exo-N-{8-[4-(7-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₄N₃O₃S₂Cl, 477.1; m/z found, 478.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.74-7.67 (m, 1H), 7.53-7.37 (m, 5H),7.01-6.92 (m, 1H), 3.60-3.50 (m, 2H), 3.20-3.08 (m, 2H), 2.89 (s, 3H),2.02-1.90 (m, 2H), 1.75-1.66 (m, 2H), 1.65-1.50 (m, 2H).

Example 216meso-endo-N-(8-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆N₃O₃SF, 455.2; m/z found, 456.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.85 (dd, J=8.7, 2.7 Hz, 1H), 7.70 (dd,J=8.9, 4.9 Hz, 1H), 7.40-7.34 (m, 2H), 7.28 (dt, J=9.1, 2.8 Hz, 1H),7.11-7.01 (m, 2H), 4.39-4.30 (m, 1H), 4.13-4.04 (m, 3H), 2.94-2.86 (m,3H), 2.21-2.08 (m, 2H), 1.94 (s, 3H), 1.92-1.78 (m, 3H), 1.76-1.60 (m,3H).

Example 217meso-exo-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆N₃O₄S₂F, 491.1; m/z found, 492.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.75 (dd, J=7.6, 1.4 Hz, 1H), 7.43-7.36 (m,2H), 7.38-7.25 (m, 2H), 7.10-7.02 (m, 2H), 4.19-4.08 (m, 2H), 4.02 (t,J=5.7 Hz, 2H), 2.93 (s, 3H), 2.91-2.86 (m, 3H), 2.00-1.87 (m, 4H),1.74-1.64 (m, 3H), 1.40-1.29 (m, 2H).

Example 218(R,R)-1-(5-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂N₃O₃SF, 427.1; m/z found, 428.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 7.58 (d, J=8.1 Hz, 1H),7.48 (dt, J=8.2, 5.6 Hz, 1H), 7.44-7.37 (m, 2H), 7.28-7.22 (m, 2H),7.10-7.02 (m, 2H), 4.50-4.48 (m, 0.5H), 4.37-4.32 (m, 0.5H), 4.09-4.01(m, 2H), 3.66-3.63 (m, 0.5H), 3.60-3.57 (m, 0.5H), 3.55-3.50 (m, 0.5H),3.42-3.37 (m, 0.5H), 3.11-3.05 (m, 0.5H), 3.00-2.86 (m, 3H), 3.64-2.59(m, 0.5H), 2.57-2.52 (m, 0.5H), 2.49-2.42 (m, 0.5H), 1.97 (s, 1.5H),1.86 (s, 1.5H), 1.84-1.79 (m, 0.5H), 1.77-1.72 (m, 0.5H), 1.72-1.66 (m,0.5H), 1.62-1.57 (m, 0.5H).

Example 219meso-endo-(8-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅N₄O₃SF, 456.2; m/z found, 457.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.45 (dd, J=8.8, 5.5 Hz, 1H), 7.56 (dd,J=9.9, 2.6 Hz, 1H), 7.40-7.32 (m, 2H), 7.21 (dt, J=9.1, 2.6 Hz, 1H),7.09-7.02 (m, 2H), 5.90 (d, J=6.0 Hz, 1H), 5.43-5.35 (m, 2H), 4.12-4.01(m, 2H), 3.70-3.59 (m, 1H), 3.25-3.14 (m, 2H), 2.72-2.63 (m, 2H),3.02-1.94 (m, 2H), 1.95-1.87 (m, 2H), 1.87-1.81 (m, 2H), 1.51-1.38 (m,2H).

Example 220meso-endo-(8-Methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-{2-[4-(6-methyl-benzothiazol-2-yloxy)-phenoxy]-ethyl}-amine

MS (ESI): mass calcd. for C₂₄H₂₉N₃O₄S₂, 487.2; m/z found, 488.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.72 (s, 1H), 7.58-7.49 (m, 1H), 7.43-7.36(m, 2H), 7.26-7.19 (m, 1H), 7.12-7.02 (m, 2H), 4.28-4.10 (m, 4H),3.29-3.12 (m, 2H), 2.97 (s, 3H), 2.66-2.53 (m, 2H), 2.38 (s, 3H),2.11-1.92 (m, 4H), 1.75-1.68 (m, 2H), 1.67-1.53 (m, 2H).

Example 221meso-endo-3-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₅N₄O₃SCl, 472.1; m/z found, 473.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.95-7.88 (m, 1H), 7.56-7.53 (m, 1H),7.52-7.38 (m, 4H), 7.37-7.29 (m, 1H), 6.08-6.01 (m, 1H), 4.28-4.14 (m,1H), 3.28-3.18 (m, 2H), 3.06-2.87 (m, 2H), 2.01-1.42 (m, 6H).

Example 222meso-endo-N-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆N₃O₄S₂Cl, 507.1; m/z found, 508.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.07 (d, J=1.7 Hz, 1H), 7.68 (d,J=8.6 Hz, 1H), 7.46 (dd, J=8.6, 2.2 Hz, 1H), 7.42-7.32 (m, 2H),7.10-6.99 (m, 2H), 4.14-3.95 (m, 2H), 3.50-3.39 (m, 1H), 3.24-3.12 (m,2H), 3.03-2.79 (m, 3H), 2.71-2.58 (m, 2H), 2.07-1.75 (m, 6H), 1.76-1.64(m, 2H).

Example 223(R,R)-2-{4-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₃N₃O₄S₂, 445.12; m/z found, 446.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 7.90 (dd, J=8.0, 0.8 Hz, 1H), 7.67 (d, J=7.4Hz, 1H), 7.45-7.39 (m, 1H), 7.39-7.34 (m, 2H), 7.34-7.28 (m, 1H),7.08-7.02 (m, 2H), 4.16 (s, 1H), 4.06 (t, J=5.8 Hz, 2H), 3.64 (s, 1H),3.35 (dd, J=10.0, 8.6 Hz, 1H), 3.22-3.15 (m, 1H), 2.99-2.89 (m, 6H),2.71 (d, J=9.6 Hz, 1H), 1.77 (d, J=9.8 Hz, 1H), 1.66 (d, J=10.0 Hz, 1H).

Example 224meso-endo-1-(3-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₂S, 455.14; m/z found, 456.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers): 7.96 (d, J=8.6Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.36-7.42 (m, 5H), 4.70-4.61 (m, 0.5H),4.50-4.43 (m, 0.5H), 4.33-4.38 (m, 1H), 4.05-4.10 (m, 1H), 2.91 (s, 1H),2.82 (s, 3H), 2.24-2.28 (m, 1H), 1.90-1.96 (m, 7H), 1.60-1.64 (m, 3H).

Example 225meso-exo-N-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₄S₂, 507.11; m/z found, 508.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.59 (dd, J=8.1, 0.8 Hz, 1H), 7.48(td, J=8.2, 5.8 Hz, 1H), 7.43-7.36 (m, 4H), 7.29-7.22 (m, 1H), 4.16 (m,1H), 3.59 (m, 1H), 3.17 (d, J=7.4 Hz, 1H), 2.92 (s, 3H), 2.88-2.63 (m,6H), 1.67-1.73 (m, 2H).

Example 226meso-endo-3-[4-(7-Fluoro-benzothiazol-2-yloxy)-benzylamino]-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₂S, 426.15; m/z found, 427.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers): 7.61-7.57 (m, 1H),7.52-7.44 (m, 3H), 7.43-7.39 (m, 2H), 7.29-7.23 (m, 1H), 5.78 (s, 2H),4.06 (m, 2H), 3.74 (s, 2H), 2.85-2.90 (m, 1H), 2.67 (s, 0.5H), 2.33 (s,0.5H), 2.15 (d, J=7.0 Hz, 2H), 1.88-1.83 (m, 2H), 1.78-1.73 (m, 2H),1.61 (d, J=13.8 Hz, 2H).

Example 227meso-exo-N-(8-[2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl]-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₃S, 455.17; m/z found, 456.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): 7.95 (dd, J=8.8, 5.5 Hz, 1H), 7.55 (dd,J=9.9, 2.6 Hz, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.21 (td, J=9.1, 2.6 Hz,1H), 7.07 (d, J=8.9 Hz, 2H), 4.23-4.02 (m, 2H), 3.98-3.83 (m, 1H),2.90-2.67 (m, 2H), 2.01-1.85 (m, 2H), 1.76 (s, 3H), 1.56 (m, 5H).

Example 228meso-endo-[4-(6-Chloro-benzothiazol-2-yloxy)-benzyl]-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₃S₂, 477.09; m/z found, 478.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.07 (d, J=2.2 Hz, 1H), 7.68 (d,J=8.6 Hz, 1H), 7.45 (dd, J=8.7, 2.2 Hz, 1H), 7.40-7.33 (m, 2H),7.09-7.03 (m, 2H), 5.76 (d, J=8.3 Hz, 1H), 5.28 (br s, 2H), 4.07 (t,J=6.1 Hz, 2H), 3.70-3.65 (m, 1H), 3.30-3.23 (m, 2H), 2.74 (t, J=6.1 Hz,2H), 1.93-1.82 (m, 2H), 1.58-1.53 (m, 3H), 1.45-1.35 (m, 2H).

Example 229meso-exo-{8-[4-(4-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea

MS (ESI): mass calcd. for C₂₂H₂₃ClN₄O₂S, 442.17; m/z found, 443.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.98-7.93 (m, 3H), 7.60 (d, J=8.1 Hz,2H), 7.55 (m, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.05-6.00 (m, 1H), 5.51 (brs, 2H), 4.19 (m, 2H), 3.77 (m, 3H), 2.33 (m, 2H), 2.13-1.83 (m, 6H).

Example 230(S,S)-6-Fluoro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀FN₃O₃S₂, 433.09; m/z found, 434.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.86 (dd, J=8.7, 2.7 Hz, 1H), 7.71(dd, J=8.9, 4.9 Hz, 1H), 7.50-7.45 (m, 2H), 7.41-7.36 (m, 2H), 7.28 (td,J=9.1, 2.8 Hz, 1H), 4.19 (s, 1H), 3.85-3.72 (m, 2H), 3.54 (s, 1H), 3.43(dd, J=9.5, 2.3 Hz, 1H), 3.22 (dd, J=9.4, 2.2 Hz, 1H), 2.94 (s, 3H),2.79 (dd, J=9.6, 2.3 Hz, 1H), 2.63 (d, J=9.6 Hz, 1H), 1.85 (d, J=9.9 Hz,1H), 1.68 (d, J=9.9 Hz, 1H).

Example 231meso-exo-N-(8-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₃S₂, 475.14; m/z found, 476.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.96 (dd, J=8.8, 5.5 Hz, 1H), 7.55(dd, J=9.9, 2.6 Hz, 1H), 7.43-7.35 (m, 4H), 7.22 (td, J=9.1, 2.6 Hz,1H), 3.50-3.35 (m, 3H), 2.95-2.80 (m, 6H), 2.05-1.60 (m, 8H).

Example 232(S,S)-7-Fluoro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂FN₃O₃S₂, 447.11; m/z found, 448.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.59 (dd, J=8.1, 0.8 Hz, 1H), 7.48(td, J=8.2, 5.8 Hz, 1H), 7.43-7.35 (m, 4H), 7.29-7.22 (m, 1H), 4.16 (brs, 1H), 3.59 (br s, 1H), 3.20-3.15 (m, 1H), 2.92 (s, 3H), 2.89-2.63 (m,6H), 1.76 (d, J=9.7 Hz, 1H), 1.65 (d, J=9.8 Hz, 1H).

Example 233meso-endo-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₄S₂, 491.13; m/z found, 492.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.94 (dd, J=8.8, 5.5 Hz, 1H), 7.55(dd, J=10.0, 2.5 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.21 (td, J=9.1, 2.6Hz, 1H), 7.07 (d, J=9.0 Hz, 2H), 4.07 (br s, 4H), 3.00-2.90 (m, 6H),2.14 (br s, 2H), 1.95-1.85 (m, 4H), 1.76 (d, J=13.9 Hz, 2H).

Example 234meso-exo-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅ClN₄O₃S, 472.13; m/z found, 473.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.08 (d, J=2.2 Hz, 1H), 7.68 (d,J=8.6 Hz, 1H), 7.48-7.43 (m, 3H), 7.42-7.37 (m, 2H), 4.07 (br s, 2H),3.73 (br s, 2H), 2.91 (s, 5H), 2.25-2.20 (m, 2H), 2.16 (br s, 1H),1.95-1.81 (m, 6H).

Example 235(R,R)-1-(5-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₂S, 411.14; m/z found, 412.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers): 7.86 (dd, J=8.7, 2.2 Hz,1H), 7.70 (dd, J=8.9, 4.8 Hz, 1H), 7.42-7.32 (m, 4H), 7.28 (td, J=9.1,2.8 Hz, 1H), 4.51, (m, 0.5H), 4.37 (m, 0.5H), 3.70-3.50 (m, 2H),3.14-3.04 (m, 1H), 2.95-2.70 (m, 5H), 1.97 (s, 2H), 1.86 (s, 2H),1.84-1.56 (m, 2H).

Example 236(R,R)-6-Chloro-2-[4-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₀H₂₀ClN₃O₃S₂, 449.06; m/z found, 450.00[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.13-8.06 (m, 1H), 7.69 (d, J=8.6 Hz,1H), 7.52-7.44 (m, 3H), 7.43-7.37 (m, 2H), 4.19 (s, 1H), 3.83-3.74 (m,2H), 3.54 (s, 1H), 3.46-3.40 (m, 1H), 3.25-3.19 (m, 1H), 2.95 (s, 3H),2.83-2.78 (m, 1H), 2.66-2.60 (m, 1H), 1.85 (d, J=9.9 Hz, 1H), 1.69 (d,J=10.0 Hz, 1H).

Example 237meso-exo-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₃S₂, 491.11; m/z found, 492.15[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.91 (d, J=8.0 Hz, 1H), 7.54 (d,J=7.9 Hz, 1H), 7.44-7.36 (m, 4H), 7.35-7.29 (m, 1H), 4.13 (s, 2H),3.05-2.95 (m, 1H), 2.93 (s, 3H), 2.90-2.83 (m, 2H), 2.81-2.73 (m, 2H),2.00-1.89 (m, 4H), 1.72-1.64 (m, 2H), 1.46-1.36 (m, 2H).

Example 238(S,S)-6-Chloro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂ClN₃O₃S₂, 463.08; m/z found, 464.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.09 (d, J=2.2 Hz, 1H), 7.69 (d,J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.2 Hz, 1H), 7.42-7.32 (m, 4H), 4.16 (s,1H), 3.58 (s, 1H), 3.30-3.13 (m, 2H), 2.92 (s, 3H), 2.88-2.79 (m, 2H),2.78-2.62 (m, 4H), 1.79-1.61 (m, 2H).

Example 239meso-endo-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅ClN₄O₂S, 456.14; m/z found, 457.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.08 (s, 1H), 7.69 (d, J=8.7 Hz, 1H),7.51-7.42 (m, 1H), 7.40-7.26 (m, 4H), 5.96-5.81 (m, 1H), 5.39 (s, 2H),3.72-3.57 (m, 1H), 3.17 (s, 2H), 2.82-2.67 (m, 2H), 2.06-1.73 (m, 6H),1.46 (d, J=13.8, 2H).

Example 240meso-exo-N-(8-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₃S, 471.14; m/z found, 472.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 7.89 (d, J=8.0Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.47-7.38 (m, 2H), 7.31 (t, J=8.0 Hz,1H), 7.15-7.01 (m, 2H), 4.41-4.29 (m, 1H), 4.16-4.02 (m, 3H), 2.98-2.81(m, 3H), 2.23-2.03 (m, 2H), 1.94 (m, 3H), 1.91-1.78 (m, 4H), 1.78-1.58(m, 3H).

Example 241(R,R)-4-Fluoro-2-{4-[2-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂FN₃O₃S₂, 447.11; m/z found, 448.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 7.79-7.74 (m,1H), 7.43-7.27 (m, 6H), 4.15 (s, 1H), 3.58 (s, 1H), 3.20-3.12 (m, 1H),2.92 (d, J=2.7 Hz, 3H), 2.87-2.62 (m, 7H), 1.75 (d, J=9.8 Hz, 1H), 1.63(d, J=9.8 Hz, 1H).

Example 242meso-exo-(8-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₂S, 440.17; m/z found, 441.15[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.79 (d, J=7.7 Hz, 1H), 7.56-7.24 (m,6H), 4.20-3.92 (m, 3H), 3.25-3.05 (m, 4H), 2.33-2.14 (m, 2H), 1.87 (d,9H).

Example 243meso-6-Fluoro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄FN₃O₄S₂, 477.12; m/z found, 478.05[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.89-7.83 (m, 1H), 7.69 (dd, J=8.8,4.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.32-7.24 (m, 1H), 7.10-7.03 (m, 2H),4.16-4.03 (m, 2H), 3.43 (s, 2H), 3.16 (d, J=10.5 Hz, 2H), 2.99-2.90 (m,3H), 2.84 (s, 2H), 2.78-2.68 (m, 2H), 1.94-1.86 (m, 2H), 1.66-1.60 (m,2H).

Example 244(R,R)-5-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.96 (dd, J=8.8, 5.5 Hz, 1H),7.64-7.52 (m, 1H), 7.44-7.28 (m, 4H), 7.28-7.16 (m, 1H), 5.75 (s, 2H),4.24 (s, 1H), 3.59-3.46 (m, 1H), 3.05 (s, 1H), 2.92-2.62 (m, 5H),1.77-1.66 (m, 1H), 1.66-1.55 (m, 1H).

Example 245(R,R)-5-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁FN₄O₂S, 412.14; m/z found, 413.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.60 (d, J=8.1 Hz, 1H), 7.55-7.44 (m,1H), 7.39 (s, 4H), 7.32-7.21 (m, 1H), 5.75 (s, 2H), 4.24 (s, 1H), 3.52(s, 1H), 3.12-2.99 (m, 1H), 2.91-2.80 (m, 1H), 2.73 (s, 4H), 1.78-1.66(m, 1H), 1.65-1.52 (m, 1H).

Example 246(R,R)-5-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁ClN₄O₂S, 428.11; m/z found, 429.15[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 8.10-8.06 (m, 1H), 7.72-7.65 (m, 1H),7.47-7.43 (m, 1H), 7.40-7.31 (m, 4H), 5.75 (s, 2H), 4.23 (s, 1H), 3.51(s, 1H), 3.29-3.20 (m, 1H), 3.04 (d, J=9.3 Hz, 1H), 2.84 (d, J=9.1 Hz,1H), 2.72 (s, 4H), 1.73-1.67 (m, 1H), 1.62-1.55 (m, 1H).

Example 247meso-5-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₃S, 457.12; m/z found, 458.10[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.89 (d, J=8.0 Hz, 1H), 7.53 (d,J=7.9 Hz, 1H), 7.42 (d, J=9.0 Hz, 2H), 7.31 (t, J=8.0 Hz, 1H), 7.09 (d,J=9.1 Hz, 2H), 4.12 (t, J=5.9 Hz, 2H), 3.94 (d, J=11.9 Hz, 1H), 3.45 (d,J=11.7 Hz, 1H), 3.23 (d, J=12.1 Hz, 1H), 2.80-2.61 (m, 3H), 1.96 (s,3H), 1.92-1.75 (m, 2H), 1.64-1.49 (m, 1H), 1.45-1.31 (m, 1H).

Example 248meso-endo-{2-[4-(7-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₄S₂, 507.11; m/z found, 508.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.71-7.67 (m, 1H), 7.51-7.39 (m, 4H),7.10-7.06 (m, 2H), 4.11-4.01 (m, 4H), 2.96-2.84 (m, 6H), 2.20-2.10 (m,2H), 1.94-1.84 (m, 4H), 1.81-1.74 (m, 2H).

Example 249(R,R)-1-(5-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.2 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆, mixture of rotamers): 7.75 (d, J=7.8 Hz, 1H),7.41-7.39 (m, 2H), 7.35-7.27 (m, 2H), 7.09-7.04 (m, 2H), 4.49 (s, 0.5H),4.34 (s, 0.5H), 4.08-4.04 (m, 2H), 3.65 (s, 0.5H), 3.59 (s, 0.5H), 3.53(d, J=7.8 Hz, 0.5H), 3.40 (d, J=7.8 Hz, 0.5H), 3.09 (d, J=7.8 Hz, 0.5H),2.99-2.86 (m, 3.5H), 2.62 (d, J=7.8 Hz, 0.5H), 2.53 (d, J=7.8 Hz, 0.5H),1.97 (s, 1.5H), 1.87 (s, 1.5H), 1.83-1.79 (m, 0.5H), 1.77-1.72 (m,0.5H), 1.72-1.67 (m, 0.5H), 1.62-1.57 (m, 0.5H).

Example 250meso-1-(8-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₂S, 441.13; m/z found, 442.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.09 (d, J=7.8 Hz, 1H), 7.68 (d,J=7.8 Hz, 1H), 7.48-7.33 (m, 5H), 4.07-3.87 (m, 1H), 3.59-3.42 (m, 1H),3.41-3.19 (m, 2H), 2.94-2.45 (m, 6H), 1.98 (s, 3H), 1.95-1.77 (m, 2H),1.65-1.30 (m, 2H).

Example 251meso-exo-N-(8-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₄S₂, 491.13; m/z found, 492.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.60-7.56 (m, 1H), 7.52-7.45 (m, 1H),7.44-7.40 (m, 1H), 7.28-7.22 (m, 1H), 7.13-7.05 (m, 2H), 4.26-3.98 (m,2H), 3.56-3.44 (m, 1H), 3.38-3.11 (m, 4H), 2.89 (s, 3H), 2.80-2.57 (m,1H), 2.25-1.61 (m, 7H).

Example 252(R,R)-5-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₁ClN₄O₂S, 428.11; m/z found, 429.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.97-7.81 (m, 2H), 7.54-7.52 (m, 2H),7.41-7.38 (m, 1H), 7.32 (d, J=7.8 Hz, 2H), 4.23 (s, 1H), 3.54-3.48 (m,2H), 3.08-3.00 (m, 2H), 2.89-2.81 (m, 2H), 1.77-1.65 (m, 2H), 1.63-1.53(m, 2H).

Example 253(S,S)-1-(5-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂ClN₃O₂S, 427.11; m/z found, 428.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.92-7.88 (m, 2H), 7.55-7.52 (m, 2H),7.44-7.37 (m, 1H), 7.32-7.29 (m, 2H), 3.78-3.47 (m, 3H), 3.15-3.01 (m,1H), 3.00-2.63 (m, 3H), 1.86 (s, 3H), 1.79-1.53 (m, 3H).

Example 254meso-exo-N-(8-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₂S, 439.17; m/z found, 440.2 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.60-7.56 (m, 1H), 7.53-7.42 (m, 5H),7.31-7.24 (m, 1H), 4.14-3.93 (m, 3H), 3.21-3.06 (m, 3H), 2.54-2.47 (m,3H), 2.34-2.18 (m, 1H), 2.06-1.87 (m, 4H), 1.86-1.76 (m, 4H).

Example 255(S,S)-2-{4-[2-(5-Methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenoxy}-5-methyl-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₅N₃O₄S₂, 459.13; m/z found, 460.2 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆): 7.69 (s, 1H), 7.55 (d, J=7.8 Hz, 1H),7.40-7.30 (m, 2H), 7.26-7.20 (m, 1H), 7.09-7.01 (m, 2H), 4.18-4.03 (m,3H), 3.69-3.61 (m, 1H), 3.41-3.29 (m, 1H), 3.24-3.13 (m, 1H), 3.02-2.86(m, 3H), 2.75-2.68 (m, 1H), 2.38 (s, 3H), 1.81-1.62 (m, 2H).

Example 256meso-5-Chloro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethoxy]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₄S₂, 493.09; m/z found, 494.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.95 (d, J=7.8 Hz, 1H), 7.77 (d,J=7.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.09-7.04 (m, 2H), 4.14-4.09 (m, 2H),3.44-3.39 (m, 2H), 3.21-3.12 (m, 2H), 2.97-2.92 (m, 2H), 2.84 (s, 3H),2.76-2.69 (m, 2H), 1.93-1.87 (m, 2H), 1.66-1.60 (m, 2H).

Example 257meso-endo-3-{2-[4-(5-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₅ClN₄O₃S, 472.13; m/z found, 473.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.95 (d, J=7.8 Hz, 1H), 7.77 (d,J=7.8 Hz, 1H), 7.40-7.35 (m, 3H), 7.08-7.04 (m, 2H), 4.11-4.01 (m, 4H),2.94-2.85 (m, 3H), 2.10-2.03 (m, 2H), 1.96-1.87 (m, 2H), 1.77-1.70 (m,2H), 1.56-1.49 (m, 2H).

Example 258meso-4-Fluoro-2-[4-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-ylmethyl)-phenoxy]-benzothiazole

MS (ESI): mass calcd. for C₂₁H₂₂FN₃O₃S₂, 447.11; m/z found, 448.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 7.78 (d, J=7.8 Hz, 1H), 7.54 (d,J=7.8 Hz, 2H), 7.46-7.42 (m, 2H), 7.37-7.27 (m, 2H), 3.57 (s, 1H),3.29-3.24 (m, 2H), 3.23-3.17 (m, 2H), 3.00-2.92 (m, 2H), 2.90-2.80 (m,3H), 2.05-1.93 (m, 2H), 1.70-1.62 (m, 2H).

Example 259meso-endo-{8-[4-(5-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea

MS (ESI): mass calcd. for C₂₂H₂₃ClN₄O₂S, 442.12; m/z found, 443.2[M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): 8.00-7.95 (m, 1H), 7.79 (d, J=7.8 Hz,1H), 7.53-7.35 (m, 5H), 5.44-5.36 (m, 2H), 3.74-3.67 (m, 1H), 3.57-3.48(m, 2H), 3.10-3.02 (m, 2H), 2.08-1.82 (m, 4H), 1.54-1.45 (m, 2H).

Example 260meso-exo-{8-[4-(5-Fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-urea

MS (ESI): mass calcd. for C₂₂H₂₃FN₄OS, 426.51; m/z found, 427.3 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 10.26-10.10 (m, 1H), 8.06-7.92 (m, 1H), 7.81(s, 1H), 7.58 (s, 4H), 7.31-7.14 (m, 1H), 6.00-5.88 (m, 1H), 5.51 (s,1H), 4.20 (s, 1H), 3.83 (s, 3H), 3.61-3.50 (m, 1H), 2.44-2.27 (m, 1H),2.05-1.79 (m, 5H).

Example 261meso-endo-(8-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₄H₂₈N₄O₂S, 436.57; m/z found, 437.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.72 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.39(s, 4H), 7.24 (d, J=8.2 Hz, 1H), 6.16-5.66 (m, 2H), 5.66-5.08 (m, 2H),4.16-3.44 (m, 2H), 2.87-2.53 (m, 2H), 2.39 (s, 4H), 2.07-1.74 (m, 4H),1.73-1.20 (m, 5H).

Example 262meso-endo-(8-{2-[4-(4-Fluoro-benzothiazole-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₆FN₄O₃S, 456.53; m/z found, 457.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 8.32 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.43(s, 2H), 7.38-7.26 (m, 2H), 7.11 (s, 2H), 6.15-5.14 (m, 4H), 4.65-3.53(m, 3H), 2.37-1.12 (m, 10H).

Example 263meso-exo-1-(3-{2[4-(7-Fluoro-benzothiazole-2-yloxy)-phenoxy]-ethylamino}8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₃S, 455.55; m/z found, 456.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 8.32 (s, 1H), 7.58 (d, J=7.4 Hz, 1H),7.50-7.46 (m, 1H), 7.44-7.37 (m, 2H), 7.30-7.20 (m, 1H), 7.09-7.03 (m,2H), 4.43 (s, 1H), 4.18 (s, 1H), 4.03 (t, J=5.7 Hz, 2H), 3.04 (s, 1H),2.91 (t, J=5.6 Hz, 2H), 1.95 (s, 6H), 1.87-1.57 (m, 5H).

Example 264(S,S)-1-(5-{2-[4-(5-Chloro-benzothiazole-2-yloxy)-phenoxy]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂ClN₃O₃S, 443.95; m/z found, 444.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 8.32 (s, 1H),7.95 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.42-7.34 (m, 3H),7.09-7.02 (m, 2H), 4.49 (s, 0.5H), 4.34 (s, 0.5H), 4.05 (t, J=5.8 Hz,2H), 3.64 (s, 0.5H), 3.58 (s, 0.5H), 3.52 (d, J=9.5 Hz, 0.5H), 3.39 (d,J=12.2 Hz, 0.5H), 3.08 (d, J=9.1 Hz, 0.5H), 3.01-2.83 (m, 3H), 2.62 (d,J=9.6 Hz, 0.5H), 1.97 (s, 1.5H), 1.86 (s, 1.5H), 1.84-1.71 (m, 1H),1.71-1.57 (m, 1H).

Example 265meso-exo-N-(8-{2-[4-(5-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆ClN₃O₄S₂, 508.06; m/z found, 509.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): 7.96 (d, J=8.5 Hz, 1H), 7.77 (d,J=2.0 Hz, 1H), 7.38 (d, J=8.5 Hz, 3H), 7.07 (s, 2H), 4.52-4.32 (m, 1H),4.16-3.93 (m, 2H), 3.54-3.35 (m, 2H), 3.29-3.10 (m, 2H), 2.87 (s, 3H),2.74-2.55 (m, 2H), 2.18-1.59 (m, 7H).

Example 266meso-exo-N-(8-{2-[4-(5-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₂S, 439.55; m/z found, 440.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 8.32 (s, 1H), 7.97 (dd, J=8.8, 5.5 Hz, 1H),7.56 (dd, J=9.9, 2.6 Hz, 1H), 7.44-7.32 (m, 4H), 7.24-7.20 (m, 1H), 4.34(s, 1H), 4.08 (s, 1H), 2.93-2.72 (m, 5H), 2.08 (s, 1H), 1.93 (s, 8H),1.70-1.51 (m, 3H).

Example 267meso-exo-3-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]octane-8-carboxylicacid amide

MS (ESI): mass calcd. for C₂₃H₂₆FN₄O₃S, 456.53; m/z found, 457.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.39 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (dd,J=8.9, 4.9 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.82 (dd, J=10.4, 7.7 Hz,1H), 6.61 (d, J=9.1 Hz, 2H), 5.38 (s, 2H), 3.67-3.50 (m, 4H), 2.04 (s,4H), 1.68-1.20 (m, 6H), 1.07 (d, J=14.1 Hz, 2H).

Example 268meso-exo-1-(3-{2-[4-(6-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₂S, 472.0; m/z found, 473.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 8.07 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.6 Hz,1H), 7.45 (dd, J=8.7, 2.2 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.07 (d,J=9.0 Hz, 2H), 4.35 (s, 1H), 4.07 (t, J=5.6 Hz, 3H), 2.89 (t, J=5.7 Hz,3H), 2.27-2.04 (m, 3H), 1.94 (s, 3H), 1.90-1.80 (m, 3H), 1.77-1.56 (m,3H).

Example 269meso-exo-(8-Methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-{2-[4-(6-methyl-benxothiazol-2-yloxy)-phenyl]-ethyl}-amine

MS (ESI): mass calcd. for C₂₄H₂₉N₃O₃S₂, 471.64; m/z found, 472.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.71 (s, 1H), 7.56 (d, J=8.2 Hz, 1H),7.39-7.30 (m, 4H), 7.23 (d, J=8.0 Hz, 1H), 4.02 (s, 2H), 2.88 (s, 4H),2.76 (s, 4H), 2.38 (s, 3H), 1.99 (br s, 2H), 1.83 (br s, 4H), 1.77-1.66(m, 3H).

Example 270(S,S)-1-{5-[4-(6-Methyl-benzothiazol-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone

MS (ESI): mass calcd. for C₂₂H₂₃N₃O₂S, 393.50; m/z found, 394.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆, mixture of rotamers): 7.72 (s, 1H), 7.57 (d,J=8.2 Hz, 1H), 7.46 (s, 2H), 7.37 (d, J=6.9 Hz, 2H), 7.24 (d, J=8.3 Hz,1H), 4.53 (s, 0.5H), 4.37 (s, 0.5H), 3.75 (s, 2H), 3.63-3.43 (s, 2H),3.33 (s, 3H), 2.83 (s, 1H), 2.61-2.43 (m, 2H), 1.97 (s, 1H), 1.89 (s,3H), 1.73 (s, 1H).

Example 271meso-endo-N-(8-{2-[4-(6-Methyl-benzothiazol-2-yloxy)-phenoxy-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₅H₂₉N₃O₃S, 451.58; m/z found, 452.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆): 7.98-7.87 (m, 1H), 7.71 (s, 1H), 7.55 (d,J=8.2 Hz, 1H), 7.41 (s, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.12 (s, 2H), 4.46(s, 2H), 4.16-3.92 (m, 3H), 3.46-3.34 (m, 2H), 2.39 (s, 3H), 2.26 (br s,1H), 1.96 (br s, 6H), 1.81 (s, 4H).

Example 272meso-exo-N-{8-[4-(6-Fluoro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₃H₂₄FN₃O₂S, 425.16; m/z found, 426.10[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.67 (dd, J=8.9, 4.8 Hz, 1H), 7.60 (d,J=8.4 Hz, 2H), 7.41-7.34 (m, 3H), 7.12 (td, J=9.0, 2.7 Hz, 1H),5.68-5.53 (m, 1H), 4.31-4.15 (m, 1H), 3.73 (s, 2H), 3.43 (s, 2H),2.25-1.70 (m, 11H).

Example 273meso-endo-N-(8-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide

MS (ESI): mass calcd. for C₂₄H₂₆FN₃O₃S, 455.17; m/z found, 456.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.76 (dd, J=7.5, 1.6 Hz, 1H),7.44-7.37 (m, 2H), 7.37-7.26 (m, 2H), 7.11-7.05 (m, 2H), 4.39-4.30 (m,1H), 4.13-4.03 (m, 3H), 2.94-2.86 (m, 3H), 2.21-2.06 (m, 2H), 1.94 (s,3H), 1.91-1.77 (m, 4H), 1.77-1.60 (m, 3H).

Example 274(R,R)-1-(5-{2-[4-(5-Chloro-benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone

MS (ESI): mass calcd. for C₂₂H₂₂ClN₃O₂S, 427.11; m/z found, 428.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆, mixture of rotamers): 7.97 (d, J=8.6Hz, 1H), 7.80-7.78 (m, 1H), 7.42-7.33 (m, 5H), 4.49 (s, 0.5H), 4.34 (s,0.5H), 3.63-3.46 (m, 1.5H), 3.29 (dd, J=9.5, 2.2 Hz, 1H), 3.06 (dd,J=11.0, 1.9 Hz, 0.5H), 2.88 (ddd, J=14.9, 9.4, 2.1 Hz, 1H), 2.82-2.66(m, 4H), 2.56 (d, J=9.5 Hz, 0.5H), 2.45 (d, J=9.2 Hz, 0.5H), 1.96 (s,1.5H), 1.85 (s, 1.5H), 1.79 (d, J=9.8 Hz, 0.5H), 1.72 (d, J=9.7 Hz,0.5H), 1.67 (d, J=9.3 Hz, 0.5H), 1.58 (d, J=9.6 Hz, 0.5H).

Example 275meso-exo-1-(3-{2-[4-(4-Chloro-benzothiazol-2-yloxy)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-ethanone

MS (ESI): mass calcd. for C₂₄H₂₆ClN₃O₂S, 455.14; m/z found, 456.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.92 (dd, J=8.0, 1.1 Hz, 1H), 7.54(dd, J=7.9, 1.1 Hz, 1H), 7.46-7.37 (m, 4H), 7.33 (t, J=8.0 Hz, 1H),4.47-4.40 (m, 1H), 4.23-4.17 (m, 1H), 3.29-3.07 (m, 2H), 2.98-2.87 (m,2H), 2.85-2.77 (m, 2H), 2.01-1.89 (m, 5H), 1.89-1.57 (m, 4H), 1.43-1.30(m, 2H).

Example 276meso-exo-N-{8-[4-(5-Chloro-benzothiazol-2-yloxy)-benzyl]-8-aza-bicyclo[3.2.1]oct-3-yl}-acetamide

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₂S, 441.13; m/z found, 442.10[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.76-7.70 (m, 3H), 7.60 (d, J=8.4 Hz,1H), 7.41 (d, J=8.6 Hz, 2H), 7.29 (d, J=2.0 Hz, 0.5H), 7.27-7.26 (m,0.5H), 5.95-5.82 (m, 1H), 4.40-4.22 (m, 1H), 3.88 (s, 2H), 3.58 (s, 2H),2.35-1.83 (m, 11H).

Example 277meso-endo-N-(8-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₃S₂, 475.14; m/z found, 476.10[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.66 (dd, J=8.9, 4.8 Hz, 1H), 7.37 (dd,J=8.0, 2.6 Hz, 1H), 7.32-7.24 (m, 4H), 7.11 (dd, J=10.3, 7.7 Hz, 1H),4.51 (d, J=6.3 Hz, 1H), 3.77-3.68 (m, 1H), 3.48-3.26 (m, 2H), 2.97 (s,3H), 2.93-2.76 (m, 2H), 2.75-2.56 (m, 2H), 2.54-2.20 (m, 2H), 2.18-2.00(m, 2H), 2.00-1.72 (m, 4H).

Example 278meso-endo-(8-{2-[4-(7-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅ClN₄O₃S, 472.13; m/z found, 473.10[M+H]⁺. ¹H NMR (300 MHz, CDCl₃): 7.60-7.50 (m, 1H), 7.30-7.10 (m, 4H),6.90-7.00 (m, 2H), 5.80-5.60 (m, 1H), 4.60-4.40 (m, 2H), 4.20-4.00 (m,2H), 3.90-3.80 (m, 1H), 3.50-3.30 (m, 2H), 2.90-2.40 (m, 4H), 2.40-2.20(m, 2H), 2.20-2.00 (m, 2H), 1.90-1.60 (m, 2H).

Example 279meso-endo-{2-[4-(4-Fluoro-benzothiazol-2-yloxy)-phenyl]-ethyl}-(8-methanesulfonyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₃S₂, 475.14; m/z found, 476.10⁺. ¹HNMR (400 MHz, CDCl₃): 7.44 (dd, J=8.0, 0.9 Hz, 1H), 7.34-7.29 (m, 4H),7.25-7.19 (m, 1H), 7.15-7.08 (m, 1H), 4.20 (s, 2H), 3.20-2.89 (m, 5H),2.87 (s, 3H), 2.47-2.08 (m, 2H), 2.02 (s, 4H), 1.90-1.68 (m, 3H).

Example 280(R,R)-5-{2-[4-(Benzothiazol-2-yloxy)-phenyl]-ethyl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid amide

MS (ESI): mass calcd. for C₂₁H₂₂N₄O₂S, 394.15; m/z found, 395.10 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): 7.80-7.60 (m, 2H), 7.40-7.10 (m, 6H), 4.90-4.20(m, 3H), 3.70-3.40 (m, 2H), 3.30-3.10 (m, 1H), 3.10-2.90 (m, 1H),2.90-2.60 (m, 5H), 2.00-1.60 (m, 2H).

Example 281meso-4-Chloro-2-{4-[2-(3-methanesulfonyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-ethyl]-phenoxy}-benzothiazole

MS (ESI): mass calcd. for C₂₂H₂₄ClN₃O₃S₂, 477.09; m/z found, 478.00[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.91 (dd, J=8.0, 1.1 Hz, 1H), 7.54(dd, J=8.0, 1.1 Hz, 1H), 7.44-7.38 (m, 4H), 7.32 (t, J=8.0 Hz, 1H),3.41-3.34 (m, 2H), 3.18-3.13 (m, 2H), 2.96-2.89 (m, 2H), 2.85 (s, 3H),2.82-2.74 (m, 2H), 2.60-2.53 (m, 2H), 1.94-1.83 (m, 2H), 1.65-1.56 (m,2H).

Example 282meso-exo-(8-{2-[4-(7-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-urea

MS (ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.20[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 7.53 (d, J=8.1 Hz, 1H), 7.36-7.31 (m,1H), 7.31-7.28 (m, 2H), 7.03-6.95 (m, 3H), 5.22 (s, 1H), 4.59 (s, 2H),4.40 (t, J=4.7 Hz, 2H), 4.13-3.98 (m, 1H), 3.78 (s, 2H), 3.21-3.03 (m,2H), 2.24-2.12 (m, 2H), 2.12-2.02 (m, 2H), 2.01-1.93 (m, 4H).

Example 283meso-1-(8-{2-[4-(7-Chloro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone

MS (ESI): mass calcd. for C₂₃H₂₄ClN₃O₃S, 457.12; m/z found, 458.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.70 (dd, J=7.5, 1.5 Hz, 1H),7.52-7.39 (m, 4H), 7.13-7.06 (m, 2H), 4.13 (t, J=6.0 Hz, 2H), 3.95 (d,J=11.3 Hz, 1H), 3.49-3.41 (m, 1H), 3.39-3.31 (m, 2H), 3.23 (d, J=11.1Hz, 1H), 2.76-2.67 (m, 3H), 1.96 (s, 3H), 1.91-1.79 (m, 2H), 1.60-1.50(m, 1H), 1.45-1.34 (m, 1H).

Example 284meso-exo-N-(8-{2-[4-(6-Fluoro-benzothiazol-2-yloxy)-phenoxy]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-methanesulfonamide

MS (ESI): mass calcd. for C₂₃H₂₆FN₃O₄S₂, 491.13; m/z found, 492.10[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 7.86 (dd, J=8.7, 2.7 Hz, 1H), 7.70(dd, J=8.9, 4.9 Hz, 1H), 7.42-7.35 (m, 2H), 7.29 (td, J=9.2, 2.8 Hz,1H), 7.10-7.04 (m, 2H), 6.97 (d, J=8.3 Hz, 1H), 4.07 (t, J=6.0 Hz, 2H),3.33-3.27 (m, 3H), 2.90 (s, 3H), 2.80-2.71 (m, 2H), 1.96-1.83 (m, 2H),1.72-1.52 (m, 6H).

Biological Methods: Recombinant Human LTA₄ Hydrolase Assay for LTA₄Hydrolase Inhibitor Activity

Compounds of the present invention were tested for LTA₄ hydrolaseinhibitor activity against recombinant human LTA₄ hydrolase (rhLTA₄H).Vectors were prepared and used to express rhLTA₄H essentially asfollows: LTA₄ hydrolase encoding DNA was amplified by polymerase chainreaction (PCR) using a human placental cDNA library as a template.Oligonucleotide primers for the PCR reaction were based on the 5′-end,and the complement of the 3′-end, of the published nucleotide sequencefor the coding region of the human LTA₄ hydrolase gene (C. D. Funk etal., Proc. Natl. Acad. Sci. USA 1987, 84:6677-6681). The amplified 1.9kb DNA fragment encoding LTA₄ hydrolase was isolated and cloned into thepFastBac1 vector (Invitrogen). Recombinant baculovirus was generated asdescribed by the manufacturer, and used to infect Spodoptera frugiperda(Sf-9) cells. Recombinant LTA₄ hydrolase enzyme was purified from theinfected Sf-9 cells essentially as described by J. K. Gierse et al.(Protein Expression and Purification 1993, 4:358-366). The purifiedenzyme solution was adjusted to contain 0.29 mg/mL LTA₄ hydrolase, 50 mMTris (pH 8.0), 150 mM NaCl, 5 mM dithiothreitol, 50% glycerol, andEDTA-free Complete protease inhibitor cocktail (Roche). The specificactivity of the enzyme was about 3.8 μmol/min/mg.

LTA₄ substrate was prepared from the methyl ester of LTA₄ (CaymanChemical) by treatment with 67 equiv of NaOH under nitrogen at rt for 40min. The LTA₄ substrate in its free acid form was kept frozen at −80° C.until needed. Each compound was diluted to different concentrations inassay buffer (0.1 M potassium phosphate (pH 7.4), 5 mg/mL fatty acidfree BSA) containing 10% DMSO. A 25-uL aliquot of each compound dilutionwas incubated for 10 min at rt with an equal volume of assay buffercontaining 36 ng of recombinant human LTA₄H. The solution was thenadjusted to 200 μL with assay buffer. LTA₄ (free acid) was thawed anddiluted in assay buffer to a concentration of 357 ng/mL, and 25 μL (9ng) of LTA₄ substrate was added to the reaction mixture (totalvolume=225 μL) at time zero. Each reaction was carried out at rt for 10min. The reaction was stopped by diluting 10 μL of the reaction mixturewith 200 μL of assay buffer. LTB₄ was quantified in the diluted sampleby a commercially available enzyme-linked immunoassay (Cayman ChemicalCo.), as recommended by the manufacturer. Positive controls, underessentially identical conditions but without addition of an inhibitorcompound, and negative controls, containing all assay components exceptenzyme, were routinely run in each experiment. IC₅₀ values weredetermined by fitting the activity data at different compoundconcentrations to a 4-parameter equation using the Grafit program(Erithacus software).

Results for the compounds tested in this assay are presented in Table 1as an average of results obtained.

TABLE 1 Ex. K_(i) (μM)  1 0.006  1B 0.054  2 0.508  3 0.007  4 0.163  4D0.260  5 0.035  6 0.050  7 0.013  7B 0.010  8 0.206  9 0.003  9B 0.043 10 0.010  11 0.013  12 0.031  13 0.034  14 0.009  15 0.018  16 0.011 17 0.011  18 0.066  19 0.163  20 0.073  21 0.013  22 0.010  23 0.026 24 0.052  25 0.008  26 0.037  27 0.001  28 0.088  29 0.077  30 0.016 31 0.076  32 0.003  33 0.164  34 0.007  35 0.093  36 0.094  37 0.044 38 0.003  39 0.100  40 0.038  41 0.015  42 0.034  43 0.442  44 0.038 45 0.190  46 0.032  47 0.057  48 1.167  49 0.020  50 0.009  51 0.092 52 0.002  53 0.117  54 0.004  55 0.116  56 0.030  57 0.173  58 0.0002 59 0.174  60 0.002  61 0.027  62 0.036  63 0.021  64 0.058  65 0.064 66 0.191  67 0.201  68 0.002  69 0.450  70 0.004  71 0.025  72 0.098 73 0.033  74 0.240  75 0.095  76 0.195  77 0.012  78 0.039  79 0.059 80 0.060  81 0.162  82 0.097  83 0.055  84 0.084  85 0.450  86 0.055 87 0.036  88 0.003  89 0.006  90 0.021  91 0.050  92 0.230  93 0.034 94 0.012  95 0.036  96 0.026  97 0.033  98 0.040  99 0.221 100 0.168101 0.108 102 0.046 103 0.051 104 0.062 105 0.069 106 0.003 107 0.020108 0.097 109 0.135 110 0.088 111 0.010 112 0.002 113 0.100 114 0.033115 0.010 116 0.013 117 0.020 118 0.023 119 0.072 120 0.205 121 0.631122 0.139 123 0.097 124 2.285 125 3.618 126 0.017 127 0.273 128 0.120129 0.035 130 0.021 131 0.013 132 0.018 133 0.020 134 0.032 135 0.057136 0.024 137 0.018 138 0.029 139 0.003 140 0.019 141 0.035 142A 0.053142B 0.095 143 0.033 144 0.101 145 0.597 146 0.078 147 0.005 148 0.229149 0.079 150 0.193 151 0.154 152 0.075 153 0.167 154 0.032 155 0.170156 0.047 157 0.057 158 0.048 159 0.110 160 0.001 161 0.043 162 0.188163 0.086 164 0.417 165 0.414 166 1.900 167 0.033 168 0.128 169 0.693170 0.090 171 0.224 172 1.055 173 0.973 174 0.196 175 0.053 176 0.431177 0.094 178 0.900 179 0.047 180 0.124 181 1.467 182 1.590 183 0.383184 0.406 185 0.965 186 0.010 187 0.975 188 0.004 189 0.375 190 0.016191 0.032 192 >10 193 0.612 194 3.139 195 1.663 196 0.793 197 0.085 1980.009 199 0.020 200 0.065 201 0.145 202 0.127 203 0.293 204 0.005 2050.394 206 1.101 207 0.006 208 0.022 209 0.069 210 0.163 211 0.159 2120.248 213 0.020 214 0.543 215 0.090 216 0.100 217 0.030 218 0.020 2190.015 220 0.445 221 0.802 222 0.130 223 0.064 224 0.033 225 0.116 2260.090 227 0.008 228 1.592 229 0.020 230 0.397 231 0.017 232 0.072 2330.225 234 0.072 235 0.023 236 0.169 237 0.244 238 0.651 239 0.130 2400.510 241 0.281 242 0.398 243 0.061 244 0.012 245 0.012 246 0.040 2470.167 248 3.127 249 0.011 250 0.232 251 0.033 252 0.108 253 2.600 2540.115 255 0.277 256 1.709 257 0.490 258 0.008 259 0.058 260 0.026 2610.100 262 0.012 263 0.190 264 0.212 265 0.310 266 0.064 267 0.296 2680.360 269 0.630 270 0.072 271 0.079 272 0.006 273 0.016 274 0.121 2750.264 276 0.038 277 0.017 278 1.739 279 0.021 280 0.011 281 2.041 2820.008 283 0.338 284 0.029

While the invention has been illustrated by reference to examples, it isunderstood that the invention is intended not to be limited to theforegoing detailed description.

1. A chemical entity selected from compounds of Formula (I),pharmaceutically acceptable salts of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I):

wherein R¹ is H; —CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂-aryl substitutedwith CO₂R^(a); —C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH;—C(O)C(R^(a))(R^(b))—F; —C(O)C(R^(a))(R^(b))—CF₃;—C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—N(R^(c))R^(d);—C(O)N(R^(c))(R^(d)); —C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl)optionally substituted with methyl; —C(O)-(monocyclic heterocycloalkyl)optionally substituted with methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl;—SO₂NH₂; —SO₂-cycloalkyl; or —SO₂— (monocyclic heteroaryl) optionallysubstituted with methyl; where R^(a) and R^(b) are each independently Hor methyl; or R^(a) and R^(b) taken together with the carbon to whichthey are attached form a saturated monocyclic cycloalkyl orheterocycloalkyl ring, optionally substituted with one or two methylgroups; R^(c) is H; and R^(d) is H, C₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O)CF₃,or —(CH₂)₀₋₁-monocyclic heteroaryl optionally substituted with one ortwo methyl groups; X is N or >CHNR^(e)—; where R^(e) is H or methyl; Zis N or >CHNR^(f)—; where R^(f) is H or methyl; and at least one of Xand Z is N; m, n, p, and q are independently 0, 1, or 2 wherein the sum(m+n+p+q) may not exceed 6; and provided that when the sum of m, n, p,and q is 2, then Y is a bond, —CH₂—, or —CH₂CH₂—; and when the sum of m,n, p, and q is 4, 5 or 6, then Y is a bond; Q is O or CH₂, and said Q islinked at the “a” or “b” position of the phenyl ring; D is O; R² is H,CH₃, OCH₃, halo, OH, NH₂, or CN; R³ is H or F; and A is —CH₂—, —CH₂CH₂—,or —OCH₂CH₂—.
 2. A chemical entity as in claim 1, wherein R¹ is H;—CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂-aryl substituted with CO₂R^(a);—C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH; —C(O)C(R^(a))(R^(b))—F;—C(O)C(R^(a))(R^(b))—CF₃; —C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl;—C(O)C(R^(a))(R^(b))—N(R^(c))R^(d); —C(O)NH₂; —C(O)-cycloalkyl;—C(O)-(monocyclic heteroaryl) optionally substituted with methyl;—C(O)-(monocyclic heterocycloalkyl) optionally substituted with methylor —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl; —SO₂NH₂; —SO₂-cycloalkyl; or—SO₂—(monocyclic heteroaryl) optionally substituted with methyl; whereR^(a) and R^(b) are each independently H or methyl; or R^(a) and R^(b)taken together with the carbon to which they are attached form asaturated monocyclic cycloalkyl; R^(c) is H; and R^(d) is H, C₁₋₄alkyl,—CO₂C₁₋₄alkyl, —C(O)CF₃, or —(CH₂)₀₋₁-monocyclic heteroaryl optionallysubstituted with one or two methyl groups.
 3. A chemical entity as inclaim 1, wherein R¹ is H; —CH₂-aryl substituted with CO₂R^(a);—C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH; —C(O)C(R^(a))(R^(b))—F;—C(O)C(R^(a))(R^(b))—CF₃; —C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl;—C(O)C(R^(a))(R^(b))—N(R^(c))R^(d); —C(O)N(R^(c))(R^(d));—C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl) optionally substitutedwith methyl; —C(O)-(monocyclic heterocycloalkyl) optionally substitutedwith methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl; —SO₂NH₂; —SO₂-cycloalkyl;or —SO₂— (monocyclic heteroaryl) optionally substituted with methyl;where R^(a) and R^(b) are each independently H or methyl; or R^(a) andR^(b) taken together with the carbon to which they are attached form asaturated monocyclic cycloalkyl or heterocycloalkyl ring, optionallysubstituted with one or two methyl groups; R^(c) is H; and R^(d) is H,—CO₂C₁₋₄alkyl, —C(O)CF₃, or —(CH₂)₀₋₁-monocyclic heteroaryl optionallysubstituted with one or two methyl groups.
 4. A chemical entity as inclaim 1, wherein R¹ is H, acetyl, 2-hydroxyacetyl, 2-fluoro-acetyl,carboxymethyl, 3,3,3-trifluoro-propionyl, 2 hydroxy-2-methyl-propionyl,tetrahydro-furan-3-carbonyl, tetrahydro-furan-2-carbonyl,tetrahydro-pyran-4-carbonyl, 2-tert-butoxycarbonylamino-acetyl,2-methoxy-acetyl, 2-amino-acetyl, carbamoyl, methanesulfonyl,tert-butoxycarbonylmethyl, 1H-pyrrole-2-carbonyl,1-methyl-1H-pyrrole-2-carbonyl, 1-methyl-1H-pyrrole-3-carbonyl, 1tert-butoxycarbonyl-azetidine-3-carbonyl,2-(2,2,2-trifluoro-acetylamino)-acetyl, azetidine-3-carbonyl,cyclobutanecarbonyl, furan-2-carbonyl, furan-3-carbonyl,pyrazine-2-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl,cyclopropanecarbonyl, isoxazole-5-carbonyl, morpholine-4-carbonyl,sulfamoyl, pyridine-3-sulfonyl, furan-2-sulfonyl,1-methyl-1H-imidazole-2-sulfonyl, 1-methyl-1H-pyrrole-2-sulfonyl,thiophene-2-sulfonyl, thiophene-3-sulfonyl, cyclopropanesulfonyl,

methoxycarbonylmethyl, ethoxycarbonylmethyl, or3-methoxycarbonyl-propyl.
 5. A chemical entity as in claim 1, wherein

is 2,5-diaza-bicyclo[2.2.1]heptane, 8-aza-bicyclo[3.2.1]oct-3-ylamine,3,8-diaza-bicyclo[3.2.1]octane, octahydro-pyrrolo[3,4-b]pyrrole,octahydro-pyrrolo[3,4-c]pyrrole, octahydro-pyrrolo[3,4-c]pyridine, ordecahydro-[1,6]naphthyridine, or 3-aza-bicyclo[3.1.0]hex-6-ylamine.
 6. Achemical entity as in claim 1, wherein R¹ is acetyl or carbamoyl.
 7. Achemical entity as in claim 1, wherein

is (S,S)-2,5-diaza-bicyclo[2.2.1]heptane, or(R,R)-2,5-diaza-bicyclo[2.2.1]heptane.
 8. A chemical entity as in claim1, wherein R² is H, CH₃, OH, OCH₃, CN, NH₂, fluoro, or chloro.
 9. Achemical entity as in claim 1, wherein Q is O and is linked at the a orb position and A is —CH₂—.
 10. A chemical entity as in claim 1, whereinQ is O and is linked at the a or b position and A is —OCH₂CH₂—.
 11. Achemical entity as in claim 1, wherein Q is O and is linked at the a orb position and A is —CH₂CH₂—.
 12. A chemical entity as in claim 1,wherein Q is —CH₂— and is linked at the a or b position and A is —CH₂—.13. A chemical entity as in claim 1, wherein Q is —CH₂— and is linked atthe a or b position and A is —OCH₂CH₂—.
 14. A chemical entity as inclaim 1, wherein Q is —CH₂— and is linked at the a or b position and Ais —CH₂CH₂—.
 15. A chemical entity as in claim 1, wherein R³ is fluoro.16. A pharmaceutical composition comprising an effective amount of atleast one chemical entity selected from the group consisting ofcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I):

wherein R¹ is H; —CH₂CO₂H; —(CH₂)₁₋₃CO₂C₁₋₄alkyl; —CH₂-aryl substitutedwith CO₂R^(a); —C(O)C₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—OH;—C(O)C(R^(a))(R^(b))—F; —C(O)C(R^(a))(R^(b))—CF₃;—C(O)C(R^(a))(R^(b))—OC₁₋₄alkyl; —C(O)C(R^(a))(R^(b))—N(R^(c))R^(d);—C(O)N(R^(c))(R^(d)); —C(O)-cycloalkyl; —C(O)-(monocyclic heteroaryl)optionally substituted with methyl; —C(O)-(monocyclic heterocycloalkyl)optionally substituted with methyl or —CO₂C₁₋₄alkyl; —SO₂C₁₋₄alkyl;—SO₂NH₂; —SO₂-cycloalkyl; or —SO₂— (monocyclic heteroaryl) optionallysubstituted with methyl; where R^(a) and R^(b) are each independently Hor methyl; or R^(a) and R^(b) taken together with the carbon to whichthey are attached form a saturated monocyclic cycloalkyl orheterocycloalkyl ring, optionally substituted with one or two methylgroups; R^(c) is H; and R^(d) is H, C₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O)CF₃,or —(CH₂)₀₋₁-monocyclic heteroaryl optionally substituted with one ortwo methyl groups; X is N or >CHNR^(e)—; where R^(e) is H or methyl; Zis N or >CHNR^(f)—; where R^(f) is H or methyl; and at least one of Xand Z is N; m, n, p, and q are independently 0, 1, or 2 wherein thetotal sum may not exceed 6; and provided that when the sum of m, n, p,and q is 2, then Y is a bond, —CH₂—, or —CH₂CH₂—; and when the sum of m,n, p, and q is 4, 5 or 6, then Y is a bond; Q is O or CH₂, and said Q islinked at the “a” or “b” position of the phenyl ring; D is O; R² is H,CH₃, OCH₃, halo, OH, NH₂, or CN; R³ is H or F; and A is —CH₂—, —CH₂CH₂—,or —OCH₂CH₂—.
 17. A chemical entity selected from the group consistingof:meso-endo-N-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-acetamide;and pharmaceutically acceptable salts, and pharmaceutically acceptableprodrugs thereof.
 18. A method for modulating leukotriene A4 hydrolaseactivity, comprising exposing leukotriene A4 hydrolase to an effectiveamount of at least one chemical entity as claimed in claim
 1. 19. Amethod as in claim 18, wherein the LTA₄H is in a subject with a disease,disorder, or medical condition mediated by LTA₄H activity.
 20. A methodfor modulating leukotriene A4 hydrolase activity, wherein theleukotriene A4 hydrolase is in a subject with a disease, disorder, ormedical condition mediated by LTA4H activity, comprising exposingleukotriene A4 hydrolase to a least one chemical entity as claimed inclaim
 17. 21. A pharmaceutical composition comprising an effectiveamount of at least one chemical entity selected from the groupconsisting of:meso-endo-N-[8-(4-Benzooxazol-2-ylmethyl-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-acetamide;and pharmaceutically acceptable salts, and pharmaceutically acceptableprodrugs, thereof.